rs199422217
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PP5_Very_StrongBP4
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
NM_001099287.2 missense
Scores
4
11
2
Clinical Significance
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]
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ACMG classification
Classification made for transcript
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 | UniProt |
---|---|---|---|---|---|---|---|
NIPAL4 | NM_001099287.2 | c.341C>A | p.Ala114Asp | missense_variant | 4/6 | ENST00000311946.8 | |
NIPAL4 | NM_001172292.2 | c.284C>A | p.Ala95Asp | missense_variant | 3/5 | ||
NIPAL4 | XM_011534552.2 | c.32C>A | p.Ala11Asp | missense_variant | 4/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NIPAL4 | ENST00000311946.8 | c.341C>A | p.Ala114Asp | missense_variant | 4/6 | 1 | NM_001099287.2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000775 AC: 118AN: 152192Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000652 AC: 160AN: 245384Hom.: 0 AF XY: 0.000628 AC XY: 84AN XY: 133840
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00115 AC: 1671AN: 1456064Hom.: 1 Cov.: 29 AF XY: 0.00109 AC XY: 789AN XY: 724712
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Data not reliable, filtered out with message: AS_VQSR
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GnomAD4 genome ? AF: 0.000775 AC: 118AN: 152310Hom.: 0 Cov.: 32 AF XY: 0.000658 AC XY: 49AN XY: 74492
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:15Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive congenital ichthyosis 6 Pathogenic:9
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, 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 | 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, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 13, 2022 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2007 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The NIPAL4 c.527C>A (p.Ala176Asp) variant has been reported in heterozygous state in individuals affected with Autosomal recessive congenital ichthyosis (Dalila Maier et al). Experimental studies have shown that this missense decreases the affinity of the NIPAL4 protein (Mauldin EA et al.). This variant has been submitted allele frequency 0.07% in the gnomAD and novel in 1000 genome database. It has been submitted to ClinVar as pathogenic. The amino acid Ala at position 176 is changed to a Asp changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Ala176Asp in NIPAL4 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic - |
Pathogenic, no assertion criteria provided | clinical testing | Genomics England Pilot Project, Genomics England | - | - - |
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. - |
not provided Pathogenic:5
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) - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 17, 2016 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
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 | Invitae | 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. - |
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 | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
D
MutationTaster
Benign
A;A;A
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D
REVEL
Pathogenic
Sift
Uncertain
D;T
Sift4G
Uncertain
D;D
Polyphen
P;P
Vest4
MVP
MPC
1.1
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at