rs199422217

Positions:

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

Variant summary

Our verdict is Likely pathogenic. Variant got 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:16 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]

NIPAL4 (HGNC:):

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

Verdict is Likely_pathogenic. Variant got 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/exons	MANE	Protein	UniProt
NIPAL4	NM_001099287.2	c.341C>A	p.Ala114Asp	missense_variant	4/6	ENST00000311946.8	NP_001092757.2
NIPAL4	NM_001172292.2	c.284C>A	p.Ala95Asp	missense_variant	3/5		NP_001165763.2
NIPAL4	XM_011534552.2	c.32C>A	p.Ala11Asp	missense_variant	4/6		XP_011532854.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NIPAL4	ENST00000311946.8	c.341C>A	p.Ala114Asp	missense_variant	4/6	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

GnomAD3 exomes AF: 0.000652 AC: 160 AN: 245384 Hom.: 0 AF XY: 0.000628 AC XY: 84 AN XY: 133840

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 SAS exome AF: 0.000525

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

Gnomad4 AMR exome AF: 0.000314

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000488

Gnomad4 FIN exome AF: 0.000324

Gnomad4 NFE exome AF: 0.00139

Gnomad4 OTH exome AF: 0.000948

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

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.000376

Gnomad4 NFE AF: 0.00140

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00105 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:16 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive congenital ichthyosis 6 Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 31, 2017	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2007	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 13, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 26, 2020	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 -
Pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Apr 07, 2022	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. -
Pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Institute for Human Genetics, University Medical Center Freiburg	May 16, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 01, 2017	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	May 20, 2023	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. -

not provided Pathogenic:6

Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 08, 2024	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; Invitae). 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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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. -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 17, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jun 02, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 16, 2020	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) -

Lamellar ichthyosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Apr 11, 2023

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

not provided, no classification provided

literature only

GeneReviews

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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

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;