5-157472861-T-C

Position:

• chr5-157472861-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001099287.2(NIPAL4):​c.1116T>C​(p.Val372=) 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

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

Verdict is Benign. Variant got -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 id is 257434.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-157472861-T-C is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
NIPAL4	NM_001099287.2	c.1116T>C	p.Val372=	synonymous_variant	6/6	ENST00000311946.8
NIPAL4	NM_001172292.2	c.1059T>C	p.Val353=	synonymous_variant	5/5
NIPAL4	XM_011534552.2	c.807T>C	p.Val269=	synonymous_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NIPAL4	ENST00000311946.8	c.1116T>C	p.Val372=	synonymous_variant	6/6	1	NM_001099287.2	P1
NIPAL4	ENST00000435489.7	c.1059T>C	p.Val353=	synonymous_variant	5/5	2
ADAM19	ENST00000517951.5	c.*1741+15404A>G		intron_variant, NMD_transcript_variant		2

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

GnomAD3 exomes AF: 0.978 AC: 216322 AN: 221182 Hom.: 105808 AF XY: 0.978 AC XY: 115176 AN XY: 117798

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 SAS exome AF: 0.991

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

Gnomad4 AFR exome AF: 0.995

Gnomad4 AMR exome AF: 0.985

Gnomad4 ASJ exome AF: 0.979

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.990

Gnomad4 FIN exome AF: 0.980

Gnomad4 NFE exome AF: 0.960

Gnomad4 OTH exome AF: 0.972

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

Gnomad4 AFR AF: 0.993

Gnomad4 AMR AF: 0.986

Gnomad4 ASJ AF: 0.978

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.993

Gnomad4 FIN AF: 0.983

Gnomad4 NFE AF: 0.964

Gnomad4 OTH AF: 0.982

Alfa AF: 0.969 Hom.: 80530

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

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Autosomal recessive congenital ichthyosis 6 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.4
DANN	Benign	0.67

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

Publications

LitVar

Other links and lift over

dbSNP: rs4704870; hg19: chr5-156899869;