rs6860507

chr5-157471682-A-Gchr5-157471682-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001099287.2(NIPAL4):c.451A>G(p.Arg151Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.479 in 1,605,988 control chromosomes in the GnomAD database, including 186,372 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R151R) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.48 (17426 hom., cov: 31)
  • Exomes 𝑓: 0.48 (168946 hom.)
• Consequence: NIPAL4 NM_001099287.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.01

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.1832983E-6).
• BP6: Variant 5-157471682-A-G is Benign according to our data. Variant chr5-157471682-A-G is described in ClinVar as [Benign]. Clinvar id is 257436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-157471682-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.711 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NIPAL4	NM_001099287.2	c.451A>G	p.Arg151Gly	missense_variant	5/6	ENST00000311946.8
NIPAL4	NM_001172292.2	c.394A>G	p.Arg132Gly	missense_variant	4/5
NIPAL4	XM_011534552.2	c.142A>G	p.Arg48Gly	missense_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NIPAL4	ENST00000311946.8	c.451A>G	p.Arg151Gly	missense_variant	5/6	1	NM_001099287.2	P1
NIPAL4	ENST00000435489.7	c.394A>G	p.Arg132Gly	missense_variant	4/5	2
ADAM19	ENST00000517951.5	c.*1741+16583T>C		intron_variant, NMD_transcript_variant		2
NIPAL4	ENST00000519150.1	c.*150A>G		3_prime_UTR_variant, NMD_transcript_variant	6/7	5

Frequencies

GnomAD3 genomes AF: 0.475 AC: 72122 AN: 151724 Hom.: 17415 Cov.: 31

Gnomad AFR AF: 0.420

Gnomad AMI AF: 0.490

Gnomad AMR AF: 0.493

Gnomad ASJ AF: 0.537

Gnomad EAS AF: 0.730

Gnomad SAS AF: 0.427

Gnomad FIN AF: 0.494

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.482

Gnomad OTH AF: 0.479

GnomAD3 exomes AF: 0.496 AC: 118724 AN: 239242 Hom.: 29945 AF XY: 0.491 AC XY: 63563 AN XY: 129338

Gnomad AFR exome AF: 0.419

Gnomad AMR exome AF: 0.492

Gnomad ASJ exome AF: 0.541

Gnomad EAS exome AF: 0.738

Gnomad SAS exome AF: 0.422

Gnomad FIN exome AF: 0.487

Gnomad NFE exome AF: 0.487

Gnomad OTH exome AF: 0.491

GnomAD4 exome AF: 0.479 AC: 696737 AN: 1454146 Hom.: 168946 Cov.: 35 AF XY: 0.478 AC XY: 345107 AN XY: 722530

Gnomad4 AFR exome AF: 0.413

Gnomad4 AMR exome AF: 0.494

Gnomad4 ASJ exome AF: 0.538

Gnomad4 EAS exome AF: 0.701

Gnomad4 SAS exome AF: 0.420

Gnomad4 FIN exome AF: 0.489

Gnomad4 NFE exome AF: 0.475

Gnomad4 OTH exome AF: 0.479

GnomAD4 genome AF: 0.475 AC: 72179 AN: 151842 Hom.: 17426 Cov.: 31 AF XY: 0.478 AC XY: 35457 AN XY: 74204

Gnomad4 AFR AF: 0.420

Gnomad4 AMR AF: 0.494

Gnomad4 ASJ AF: 0.537

Gnomad4 EAS AF: 0.730

Gnomad4 SAS AF: 0.426

Gnomad4 FIN AF: 0.494

Gnomad4 NFE AF: 0.482

Gnomad4 OTH AF: 0.479

Alfa AF: 0.487 Hom.: 43936

Bravo AF: 0.471

ESP6500AA AF: 0.417 AC: 1701

ESP6500EA AF: 0.465 AC: 3906

ExAC AF: 0.486 AC: 58781

Asia WGS AF: 0.572 AC: 1991 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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

Autosomal recessive congenital ichthyosis 6 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
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. -

not provided Benign:2

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.045
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	13
Dann	Benign	0.81
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.53	T;T
MetaRNN	Benign	0.0000072	T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	3.9e-20	P;P;P
PrimateAI	Benign	0.44	T
PROVEAN	Benign	2.0	N;N
REVEL	Benign	0.13
Sift	Benign	0.66	T;T
Sift4G	Benign	0.73	T;T
Polyphen		0.0	B;B
Vest4		0.092
MPC		0.35
ClinPred		0.00097	T
GERP RS		4.8
Varity_R		0.26
gMVP		0.42

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: rs6860507; hg19: chr5-156898690;