5-157472861-T-C

Variant names:

• chr5-157472861-T-C
• rs4704870
• NM_001099287.2:c.1116T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001099287.2(NIPAL4):​c.1116T>C​(p.Val372Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.967 in 1,573,488 control chromosomes in the GnomAD database, including 736,012 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.98 (72854 hom., cov: 30)
  • Exomes 𝑓: 0.97 (663158 hom.)
• Consequence: NIPAL4 NM_001099287.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.748
• Publications: 18 publications found

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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 5-157472861-T-C is Benign according to our data. Variant chr5-157472861-T-C is described in ClinVar as Benign. ClinVar VariationId is 257434.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.748 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.985 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPAL4	NM_001099287.2	c.1116T>C	p.Val372Val	synonymous_variant	Exon 6 of 6	ENST00000311946.8	NP_001092757.2
NIPAL4	NM_001172292.2	c.1059T>C	p.Val353Val	synonymous_variant	Exon 5 of 5		NP_001165763.2
NIPAL4	XM_011534552.2	c.807T>C	p.Val269Val	synonymous_variant	Exon 6 of 6		XP_011532854.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NIPAL4	ENST00000311946.8	c.1116T>C	p.Val372Val	synonymous_variant	Exon 6 of 6	1	NM_001099287.2	ENSP00000311687.8
NIPAL4	ENST00000435489.7	c.1059T>C	p.Val353Val	synonymous_variant	Exon 5 of 5	2		ENSP00000406456.3
ADAM19	ENST00000517951.5	n.*1741+15404A>G		intron_variant	Intron 21 of 22	2		ENSP00000428376.1

Frequencies

GnomAD3 genomes AF: 0.978 AC: 148788 AN: 152094 Hom.: 72793 Cov.: 30

Gnomad AFR AF: 0.993

Gnomad AMI AF: 0.990

Gnomad AMR AF: 0.986

Gnomad ASJ AF: 0.978

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.993

Gnomad FIN AF: 0.983

Gnomad MID AF: 0.997

Gnomad NFE AF: 0.964

Gnomad OTH AF: 0.982

GnomAD2 exomes AF: 0.978 AC: 216322 AN: 221182 AF XY: 0.978

Gnomad AFR exome AF: 0.994

Gnomad AMR exome AF: 0.986

Gnomad ASJ exome AF: 0.980

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.982

Gnomad NFE exome AF: 0.966

Gnomad OTH exome AF: 0.972

GnomAD4 exome AF: 0.966 AC: 1372852 AN: 1421276 Hom.: 663158 Cov.: 42 AF XY: 0.967 AC XY: 677775 AN XY: 700934

African (AFR) AF: 0.995 AC: 32648 AN: 32824

American (AMR) AF: 0.985 AC: 42164 AN: 42790

Ashkenazi Jewish (ASJ) AF: 0.979 AC: 22621 AN: 23098

East Asian (EAS) AF: 1.00 AC: 39294 AN: 39296

South Asian (SAS) AF: 0.990 AC: 77853 AN: 78624

European-Finnish (FIN) AF: 0.980 AC: 50648 AN: 51676

Middle Eastern (MID) AF: 0.997 AC: 5565 AN: 5580

European-Non Finnish (NFE) AF: 0.960 AC: 1045088 AN: 1088778

Other (OTH) AF: 0.972 AC: 56971 AN: 58610

GnomAD4 genome AF: 0.978 AC: 148908 AN: 152212 Hom.: 72854 Cov.: 30 AF XY: 0.980 AC XY: 72903 AN XY: 74410

African (AFR) AF: 0.993 AC: 41216 AN: 41516

American (AMR) AF: 0.986 AC: 15094 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.978 AC: 3395 AN: 3470

East Asian (EAS) AF: 1.00 AC: 5170 AN: 5170

South Asian (SAS) AF: 0.993 AC: 4793 AN: 4826

European-Finnish (FIN) AF: 0.983 AC: 10411 AN: 10590

Middle Eastern (MID) AF: 0.997 AC: 293 AN: 294

European-Non Finnish (NFE) AF: 0.964 AC: 65566 AN: 68026

Other (OTH) AF: 0.982 AC: 2067 AN: 2104

Alfa AF: 0.970 Hom.: 101830

Bravo AF: 0.979

Asia WGS AF: 0.995 AC: 3462 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal recessive congenital ichthyosis 6 Benign:2

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.4
DANN	Benign	0.67
PhyloP100		0.75
Mutation Taster		=38/62	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs4704870; hg19: chr5-156899869; COSMIC: COSV108034872; COSMIC: COSV108034872;