5-157472917-C-T

Position:

chr5-157472917-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. 13/20 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.645

Variant links:

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]

NIPAL4 links:

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]

ADAM19 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 257435.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-157472917-C-T is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
NIPAL4	NM_001099287.2 linkuse as main transcript	c.1172C>T	p.Ser391Leu	missense_variant	6/6	ENST00000311946.8	NP_001092757.2	Q0D2K0-1
NIPAL4	NM_001172292.2 linkuse as main transcript	c.1115C>T	p.Ser372Leu	missense_variant	5/5		NP_001165763.2	Q0D2K0-2
NIPAL4	XM_011534552.2 linkuse as main transcript	c.863C>T	p.Ser288Leu	missense_variant	6/6		XP_011532854.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NIPAL4	ENST00000311946.8 linkuse as main transcript	c.1172C>T	p.Ser391Leu	missense_variant	6/6	1	NM_001099287.2	ENSP00000311687.8	Q0D2K0-1
NIPAL4	ENST00000435489.7 linkuse as main transcript	c.1115C>T	p.Ser372Leu	missense_variant	5/5	2		ENSP00000406456.3	Q0D2K0-2
ADAM19	ENST00000517951.5 linkuse as main transcript	n.*1741+15348G>A		intron_variant		2		ENSP00000428376.1	E5RIS2

Frequencies

GnomAD3 genomes

AF:

0.0894

AC:

13592

AN:

152066

Hom.:

903

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0630

AC:

11150

AN:

176962

Hom.:

585

AF XY:

0.0633

AC XY:

5927

AN XY:

93692

show subpopulations

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 SAS exome

AF:

0.118

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.:

AF XY:

0.0616

AC XY:

41453

AN XY:

672580

show subpopulations

Gnomad4 AFR exome

AF:

0.194

Gnomad4 AMR exome

AF:

0.0481

Gnomad4 ASJ exome

AF:

0.0628

Gnomad4 EAS exome

AF:

0.000976

Gnomad4 SAS exome

AF:

0.115

Gnomad4 FIN exome

AF:

0.0291

Gnomad4 NFE exome

AF:

0.0559

Gnomad4 OTH exome

AF:

0.0716

GnomAD4 genome

AF:

0.0895

AC:

13615

AN:

152184

Hom.:

907

Cov.:

AF XY:

0.0887

AC XY:

6598

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.186

Gnomad4 AMR

AF:

0.0608

Gnomad4 ASJ

AF:

0.0657

Gnomad4 EAS

AF:

0.00212

Gnomad4 SAS

AF:

0.109

Gnomad4 FIN

AF:

0.0238

Gnomad4 NFE

AF:

0.0543

Gnomad4 OTH

AF:

0.114

Alfa

AF:

0.0585

Hom.:

449

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

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Autosomal recessive congenital ichthyosis 6

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.038

.;T

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.49

T;T

MetaRNN

Benign

0.0014

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

.;N

PrimateAI

Benign

0.29

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

GERP RS

5.5

Varity_R

0.11

gMVP

0.37

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over