5-157472917-C-T

Variant names:

• chr5-157472917-C-T
• rs61743233
• NM_001099287.2:c.1172C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001099287.2(NIPAL4):​c.1172C>T​(p.Ser391Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0632 in 1,524,446 control chromosomes in the GnomAD database, including 4,153 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.089 (907 hom., cov: 32)
  • Exomes 𝑓: 0.060 (3246 hom.)
• Consequence: NIPAL4 NM_001099287.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.645
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014172196).
• BP6: Variant 5-157472917-C-T is Benign according to our data. Variant chr5-157472917-C-T is described in ClinVar as Benign. ClinVar VariationId is 257435.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.182 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIPAL4	NM_001099287.2	c.1172C>T	p.Ser391Leu	missense_variant	Exon 6 of 6	ENST00000311946.8	NP_001092757.2
NIPAL4	NM_001172292.2	c.1115C>T	p.Ser372Leu	missense_variant	Exon 5 of 5		NP_001165763.2
NIPAL4	XM_011534552.2	c.863C>T	p.Ser288Leu	missense_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.1172C>T	p.Ser391Leu	missense_variant	Exon 6 of 6	1	NM_001099287.2	ENSP00000311687.8
NIPAL4	ENST00000435489.7	c.1115C>T	p.Ser372Leu	missense_variant	Exon 5 of 5	2		ENSP00000406456.3
ADAM19	ENST00000517951.5	n.*1741+15348G>A		intron_variant	Intron 21 of 22	2		ENSP00000428376.1

Frequencies

GnomAD3 genomes AF: 0.0894 AC: 13592 AN: 152066 Hom.: 903 Cov.: 32

Gnomad AFR AF: 0.186

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0609

Gnomad ASJ AF: 0.0657

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.108

Gnomad FIN AF: 0.0238

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0543

Gnomad OTH AF: 0.115

GnomAD2 exomes AF: 0.0630 AC: 11150 AN: 176962 AF XY: 0.0633

Gnomad AFR exome AF: 0.189

Gnomad AMR exome AF: 0.0464

Gnomad ASJ exome AF: 0.0573

Gnomad EAS exome AF: 0.00250

Gnomad FIN exome AF: 0.0279

Gnomad NFE exome AF: 0.0550

Gnomad OTH exome AF: 0.0640

GnomAD4 exome AF: 0.0602 AC: 82657 AN: 1372262 Hom.: 3246 Cov.: 32 AF XY: 0.0616 AC XY: 41453 AN XY: 672580

African (AFR) AF: 0.194 AC: 5923 AN: 30572

American (AMR) AF: 0.0481 AC: 1497 AN: 31116

Ashkenazi Jewish (ASJ) AF: 0.0628 AC: 1273 AN: 20280

East Asian (EAS) AF: 0.000976 AC: 38 AN: 38946

South Asian (SAS) AF: 0.115 AC: 8142 AN: 70890

European-Finnish (FIN) AF: 0.0291 AC: 1450 AN: 49798

Middle Eastern (MID) AF: 0.104 AC: 555 AN: 5314

European-Non Finnish (NFE) AF: 0.0559 AC: 59740 AN: 1068900

Other (OTH) AF: 0.0716 AC: 4039 AN: 56446

GnomAD4 genome AF: 0.0895 AC: 13615 AN: 152184 Hom.: 907 Cov.: 32 AF XY: 0.0887 AC XY: 6598 AN XY: 74400

African (AFR) AF: 0.186 AC: 7703 AN: 41474

American (AMR) AF: 0.0608 AC: 930 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0657 AC: 228 AN: 3470

East Asian (EAS) AF: 0.00212 AC: 11 AN: 5188

South Asian (SAS) AF: 0.109 AC: 527 AN: 4824

European-Finnish (FIN) AF: 0.0238 AC: 252 AN: 10606

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0543 AC: 3695 AN: 68016

Other (OTH) AF: 0.114 AC: 240 AN: 2112

Alfa AF: 0.0686 Hom.: 962

Bravo AF: 0.0950

TwinsUK AF: 0.0542 AC: 201

ALSPAC AF: 0.0553 AC: 213

ESP6500AA AF: 0.168 AC: 638

ESP6500EA AF: 0.0538 AC: 445

ExAC AF: 0.0620 AC: 7264

Asia WGS AF: 0.0570 AC: 197 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 01, 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

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive congenital ichthyosis 6 Benign:1

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.038	.;T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.49	T;T
MetaRNN	Benign	0.0014	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	.;N
PhyloP100		0.65
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.40	N;N
REVEL	Uncertain	0.30
Sift	Benign	0.39	T;T
Sift4G	Benign	0.26	T;T
Polyphen		0.0	B;B
Vest4		0.075
MPC		0.25
ClinPred		0.029	T
GERP RS		5.5
Varity_R		0.11
gMVP		0.37
Mutation Taster		=95/5	polymorphism (auto)

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: rs61743233; hg19: chr5-156899925; COSMIC: COSV57436334; COSMIC: COSV57436334;