Genetic Variant NM_001395849.1:c.533C>G (chr16-22527961-C-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_StrongBP6_Moderate

The NM_001395849.1(NPIPB5):c.533C>G(p.Thr178Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0046 ( 0 hom., cov: 4)

Exomes 𝑓: 0.036 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NPIPB5
NM_001395849.1 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.635

Variant links:

Genes affected

NPIPB5 (HGNC:37233): (nuclear pore complex interacting protein family member B5) Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

NPIPB5 links:

LOC105371131 (HGNC:):

LOC105371131 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0028055906).

BP6

Variant 16-22527961-C-G is Benign according to our data. Variant chr16-22527961-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 3201705.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPIPB5	NM_001395849.1 link	c.533C>G	p.Thr178Ser	missense_variant	Exon 4 of 7	ENST00000424340.7	NP_001382778.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPIPB5	ENST00000424340.7 link	c.533C>G	p.Thr178Ser	missense_variant	Exon 4 of 7	1	NM_001395849.1	ENSP00000440703.1		A8MRT5

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

12592

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00570

Gnomad AMI

AF:

0.0238

Gnomad AMR

AF:

0.00546

Gnomad ASJ

AF:

0.00307

Gnomad EAS

AF:

0.00132

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00591

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00444

Gnomad OTH

AF:

0.00549

GnomAD3 exomes

AF:

0.0867

AC:

AN:

992

Hom.:

AF XY:

0.0822

AC XY:

AN XY:

596

show subpopulations

Gnomad AFR exome

AF:

0.0625

Gnomad AMR exome

AF:

0.0936

Gnomad ASJ exome

AF:

0.167

Gnomad EAS exome

AF:

0.0319

Gnomad SAS exome

AF:

0.0788

Gnomad NFE exome

AF:

0.0833

Gnomad OTH exome

AF:

0.211

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0364

AC:

2295

AN:

62964

Hom.:

Cov.:

AF XY:

0.0364

AC XY:

1246

AN XY:

34188

show subpopulations

Gnomad4 AFR exome

AF:

0.0434

Gnomad4 AMR exome

AF:

0.0311

Gnomad4 ASJ exome

AF:

0.0349

Gnomad4 EAS exome

AF:

0.00625

Gnomad4 SAS exome

AF:

0.0337

Gnomad4 FIN exome

AF:

0.0311

Gnomad4 NFE exome

AF:

0.0423

Gnomad4 OTH exome

AF:

0.0288

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00460

AC:

AN:

12602

Hom.:

Cov.:

AF XY:

0.00533

AC XY:

AN XY:

5624

show subpopulations

Gnomad4 AFR

AF:

0.00566

Gnomad4 AMR

AF:

0.00544

Gnomad4 ASJ

AF:

0.00307

Gnomad4 EAS

AF:

0.00132

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00591

Gnomad4 NFE

AF:

0.00444

Gnomad4 OTH

AF:

0.00532

ExAC

AF:

0.00382

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Oct 10, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.076

.;.;T;T;.;.

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.0011

LIST_S2

Benign

0.49

.;T;T;.;T;.

M_CAP

Benign

0.0051

MetaRNN

Benign

0.0028

T;T;T;T;T;T

MetaSVM

Benign

-0.84

PROVEAN

Uncertain

-3.1

D;.;D;D;D;.

REVEL

Benign

0.075

Sift

Uncertain

0.015

D;.;D;D;D;.

Sift4G

Uncertain

0.016

D;D;D;D;D;D

Polyphen

0.96

.;.;P;P;.;.

Vest4

0.089, 0.084, 0.086, 0.12

MutPred

0.37

Loss of methylation at K181 (P = 0.1048);Loss of methylation at K181 (P = 0.1048);Loss of methylation at K181 (P = 0.1048);Loss of methylation at K181 (P = 0.1048);Loss of methylation at K181 (P = 0.1048);.;

ClinPred

0.042

GERP RS

0.46

Varity_R

0.23

gMVP

0.0037

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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