rs199422217

Variant names:

• chr5-157468728-C-A
• rs199422217
• NM_001099287.2:c.341C>A

Your query was ambiguous. Multiple possible variants found:

• chr5-157468728-C-A
• chr5-157468728-C-G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 8P and 1B. PP5_Very_Strong BP4

The NM_001099287.2(NIPAL4):​c.341C>A​(p.Ala114Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000775 in 152,310 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00077 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: NIPAL4 NM_001099287.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:20 O:1
• Conservation: PhyloP100: 2.03

Genes affected

NIPAL4 (HGNC:28018): (NIPA like domain containing 4) This gene likely encodes a membrane receptor. Mutations in this gene have been associated with autosomal recessive congenital ichthyosis. [provided by RefSeq, Feb 2010]

ADAM19 (HGNC:197): (ADAM metallopeptidase domain 19) This gene encodes a member of the ADAM (a disintegrin and metalloprotease domain) family. Members of this family are membrane-anchored proteins structurally related to snake venom disintegrins and have been implicated in a variety of biological processes involving cell-cell and cell-matrix interactions, including fertilization, muscle development, and neurogenesis. This member is a type I transmembrane protein and serves as a marker for dendritic cell differentiation. It has been demonstrated to be an active metalloproteinase, which may be involved in normal physiological processes such as cell migration, cell adhesion, cell-cell and cell-matrix interactions, and signal transduction. It is proposed to play a role in pathological processes, such as cancer, inflammatory diseases, renal diseases, and Alzheimer's disease. [provided by RefSeq, May 2013]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PP5: Variant 5-157468728-C-A is Pathogenic according to our data. Variant chr5-157468728-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 1731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-157468728-C-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.38465208). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPAL4	NM_001099287.2	c.341C>A	p.Ala114Asp	missense_variant	Exon 4 of 6	ENST00000311946.8	NP_001092757.2
NIPAL4	NM_001172292.2	c.284C>A	p.Ala95Asp	missense_variant	Exon 3 of 5		NP_001165763.2
NIPAL4	XM_011534552.2	c.32C>A	p.Ala11Asp	missense_variant	Exon 4 of 6		XP_011532854.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NIPAL4	ENST00000311946.8	c.341C>A	p.Ala114Asp	missense_variant	Exon 4 of 6	1	NM_001099287.2	ENSP00000311687.8

Frequencies

GnomAD3 genomes AF: 0.000775 AC: 118 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00140

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000652 AC: 160 AN: 245384 AF XY: 0.000628

Gnomad AFR exome AF: 0.000135

Gnomad AMR exome AF: 0.000352

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000142

Gnomad NFE exome AF: 0.00111

Gnomad OTH exome AF: 0.000678

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00115 AC: 1671 AN: 1456064 Hom.: 1 Cov.: 29 AF XY: 0.00109 AC XY: 789 AN XY: 724712

Gnomad4 AFR exome AF: 0.0000899 AC: 3 AN: 33382

Gnomad4 AMR exome AF: 0.000314 AC: 14 AN: 44656

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26106

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39648

Gnomad4 SAS exome AF: 0.000488 AC: 42 AN: 86036

Gnomad4 FIN exome AF: 0.000324 AC: 17 AN: 52442

Gnomad4 NFE exome AF: 0.00139 AC: 1536 AN: 1107942

Gnomad4 Remaining exome AF: 0.000948 AC: 57 AN: 60096

GnomAD4 genome AF: 0.000775 AC: 118 AN: 152310 Hom.: 0 Cov.: 32 AF XY: 0.000658 AC XY: 49 AN XY: 74492

Gnomad4 AFR AF: 0.000241 AC: 0.000240604 AN: 0.000240604

Gnomad4 AMR AF: 0.000458 AC: 0.000457516 AN: 0.000457516

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000415 AC: 0.000414938 AN: 0.000414938

Gnomad4 FIN AF: 0.000376 AC: 0.000376364 AN: 0.000376364

Gnomad4 NFE AF: 0.00140 AC: 0.00139661 AN: 0.00139661

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.000869 Hom.: 0

Bravo AF: 0.000763

ESP6500AA AF: 0.000249 AC: 1

ESP6500EA AF: 0.00192 AC: 16

ExAC AF: 0.000662 AC: 80

EpiCase AF: 0.000929

EpiControl AF: 0.00148

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:20 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive congenital ichthyosis 6 Pathogenic:13

May 16, 2019

Institute for Human Genetics, University Medical Center Freiburg

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 24, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 20, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed missense c.341C>A(p.Ala114Asp) variant in NIPAL4 gene has been reported previously in homozygous and compound heterozygous states in multiple individuals affected with congenital ichthyosis (Sitek JC, et al., 2018; Diociaiuti A, et al., 2016; Wajid M, et al., 2010). This variant has been observed to segregate with disease in related individuals. The p.Ala114Asp variant has been reported with allele frequency of 0.07% in gnomAD Exomes. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). Computational evidences (Polyphen - Possibly damaging, SIFT - Tolerated and MutationTaster - Disease causing) predicts conflicting evidence on protein structure and function for this variant. The amino acid change p.Ala114Asp in NIPAL4 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ala at position 114 is changed to a Asp changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -

Jul 19, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.066%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.77; 3Cnet: 0.71). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000001731 /PMID: 15317751). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 20016120, 22622417, 24397709, 25458912, 29444371, 31168818). The variant has been reported to co-segregate with the disease in at least 5 similarly affected relatives/individuals in the same family or similarly affected unrelated family (PMID: 20016120). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Sep 01, 2017

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been previously reported as disease-causing and was found once in our laboratory homozygous in a 6-month-old female collodion baby with mild micrognathia, microstomia, hypoplastic flexion creases, congenital ichthyosis. Heterozygotes are expected to be asymptomatic carriers. -

Apr 07, 2022

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A homozygous missense variant in exon 4 of the NIPAL4 gene that results in the amino acid substitution of Aspartate for Alanine at codon 114 was detected. The observed variant c.341C>A (p.Ala114Asp) has a MAF of 0.05% and 0.07% in the 1000 genomes and gnomAD databases. The in silico prediction of the variant are possibly damaging by PolyPhen-2 (HumDiv) and damaging by LRT and MutationTaster2. The reference codon is conserved across mammals. In summary, the variant meets our criteria to be classified as pathogenic. -

-

Genomics England Pilot Project, Genomics England

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 06, 2025

Molecular Genetics, Royal Melbourne Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change in NIPAL4 is predicted to replace alanine with aspartic acid at codon 114, p.(Ala114Asp). This variant is also known as A176D, A157D and A95D. The alanine residue is moderately conserved (100 vertebrates, Multiz Alignments), and is located in a transmembrane domain. There is a large physicochemical difference between alanine and aspartic acid. The highest population minor allele frequency in the population database gnomAD v4.1 is 0.14% (1,631/1,175,964 alleles, 1 homozygote) in the European (non-Finnish) population. ClinVar contains multiple entries for this variant (Variation ID: 1731). This variant has been detected as homozygous and compound heterozygous in multiple individuals with congenital ichthyosis, with at least one pathogenic variant confirmed on the second allele and has been shown to segregate with disease in multiple families (PMID: 15317751, 17557927, 20016120, 29444371, 31046801). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.77). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.7.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PP1_Strong, PP3. -

May 13, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 26, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from alanine to aspartic acid (exon 4). (N) 0252 - Variant is homozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (184 heterozygotes, 0 homozygotes). (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (517 heterozygotes, 0 homozygotes). (N) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif (magnesium transporter NIPA domain (PDB, Decipher). (N) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported as one of the most common pathogenic variants in patients with ichthyosis (ClinVar, PMID: 17557927, PMID: 31046801). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Aug 31, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NIPAL4 c.527C>A (p.Ala176Asp) missense variant has been described as one of the two most common pathogenic variants for congenital ichthyosis, together accounting for up to 90% of disease alleles (Richard et al. 2014). Across a selection of the available literature, the p.Ala176Asp variant has been identified in a homozygous state in 45 patients and in a compound heterozygous state in eight patients (Lefevre et al. 2004; Dahlqvist et al. 2007; Wajid et al. 2010; Li et al. 2012; Palamar et al. 2015; Kiritsi et al. 2015; Diociaiuti et al. 2016). Up to 60% of individuals were born as collodion babies and most had clinical phenotypes consistent with lamellar ichthyosis or nonbullous congenital ichthyosiform erythroderma. The p.Ala176Asp variant was absent from 300 control chromosomes but is reported at a frequency of 0.0019 in the European American population of the Exome Sequencing Project. Epidermal expression of the ichthyin protein in skin biopsies from healthy individuals showed the enzyme predominantly expressed in the upper epidermis, while expression in individuals homozygous for the p.Ala176Asp variant showed protein in the cell periphery and cytoplasm (Li et al. 2012). Based on the evidence p.Ala176Asp variant is classified as pathogenic for congenital ichthyosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Feb 06, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided Pathogenic:6

Sep 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 176 of the NIPAL4 protein (p.Ala176Asp). This variant is present in population databases (rs199422217, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with autosomal recessive congenital ichthyosis (PMID: 15317751, 17557927, 20016120, 25458912, 26762237, 29444371, 29453417, 31046801, 31168818, 31532840, 34908195, 35412663, 35734965; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as 341C>A (A114N). ClinVar contains an entry for this variant (Variation ID: 1731). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt NIPAL4 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Jun 17, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 02, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 16, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The majority of individuals homozygous for this variant present with a collodion membrane at birth and develop generalized ichthyosis with erythema and palmoplantar keratoderma, although a lamellar ichthyosis-like phenotype has also been observed (Lefevre et al., 2004); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25458912, 24397709, 29453417, 31168818, 25525159, 17557927, 20016120, 22622417, 15317751, 22258272, 27025581, 29444371, 26762237, 25326635, 31532840) -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Lamellar ichthyosis Pathogenic:1

Apr 11, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: NIPAL4 c.341C>A (p.Ala114Asp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00065 in 245384 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in NIPAL4 causing Lamellar Ichthyosis (0.00065 vs 0.001), allowing no conclusion about variant significance. c.341C>A has been reported in the literature in multiple individuals affected with Lamellar Ichthyosis, including several homozygotic individuals (examples: Lefevre_2004, Dahlqvist_2007). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Autosomal recessive congenital ichthyosis Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Uncertain	0.089	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	.;D
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.38	T;T
MetaSVM	Uncertain	0.51	D
MutationAssessor	Uncertain	2.4	.;M
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0080	D;T
Sift4G	Uncertain	0.012	D;D
Polyphen		0.74	P;P
Vest4		0.86
MVP		0.61
MPC		1.1
ClinPred		0.051	T
GERP RS		3.9
Varity_R		0.71
gMVP		0.89
Mutation Taster		=17/83	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs199422217; hg19: chr5-156895736;