chr5-71012371-G-A

Position:

chr5-71012371-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_004536.3(NAIP):c.545C>T(p.Ser182Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000497 in 1,609,146 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0000048 ( 1 hom. )

Consequence

NAIP
NM_004536.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.82

Variant links:

Genes affected

NAIP (HGNC:7634): (NLR family apoptosis inhibitory protein) This gene is part of a 500 kb inverted duplication on chromosome 5q13. This duplicated region contains at least four genes and repetitive elements which make it prone to rearrangements and deletions. The repetitiveness and complexity of the sequence have also caused difficulty in determining the organization of this genomic region. This copy of the gene is full length; additional copies with truncations and internal deletions are also present in this region of chromosome 5q13. It is thought that this gene is a modifier of spinal muscular atrophy caused by mutations in a neighboring gene, SMN1. The protein encoded by this gene contains regions of homology to two baculovirus inhibitor of apoptosis proteins, and it is able to suppress apoptosis induced by various signals. Alternative splicing and the use of alternative promoters results in multiple transcript variants. [provided by RefSeq, Nov 2016]

NAIP links:

NAIP (HGNC:):

NAIP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.946

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NAIP	NM_004536.3 linkuse as main transcript	c.545C>T	p.Ser182Leu	missense_variant	4/17	ENST00000517649.6	NP_004527.2	Q13075-1
NAIP	NM_001346870.2 linkuse as main transcript	c.545C>T	p.Ser182Leu	missense_variant	4/17		NP_001333799.1	Q13075-1
NAIP	NM_022892.2 linkuse as main transcript	c.182+8288C>T		intron_variant			NP_075043.1	Q13075-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NAIP	ENST00000517649.6 linkuse as main transcript	c.545C>T	p.Ser182Leu	missense_variant	4/17	1	NM_004536.3	ENSP00000428657.2		Q13075-1

Frequencies

GnomAD3 genomes

AF:

0.00000660

AC:

AN:

151528

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000659

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249100

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134576

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000292

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000480

AC:

AN:

1457618

Hom.:

Cov.:

AF XY:

0.00000552

AC XY:

AN XY:

724974

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000225

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000451

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000660

AC:

AN:

151528

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73962

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000659

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 09, 2024

The c.545C>T (p.S182L) alteration is located in exon 4 (coding exon 1) of the NAIP gene. This alteration results from a C to T substitution at nucleotide position 545, causing the serine (S) at amino acid position 182 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.38

T;T;.

Eigen

Uncertain

0.34

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.95

D;.;D

M_CAP

Benign

0.010

MetaRNN

Pathogenic

0.95

D;D;D

MetaSVM

Benign

-0.97

MutationAssessor

Uncertain

2.7

M;M;.

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-2.6

D;D;D

REVEL

Benign

0.27

Sift

Uncertain

0.0030

D;D;D

Sift4G

Uncertain

0.0060

D;D;D

Polyphen

0.99

D;D;D

Vest4

0.64

MutPred

0.82

Gain of catalytic residue at S177 (P = 0.2517);Gain of catalytic residue at S177 (P = 0.2517);Gain of catalytic residue at S177 (P = 0.2517);

MVP

0.65

MPC

0.58

ClinPred

0.87

GERP RS

3.4

Varity_R

0.60

gMVP

0.72

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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