17-4933086-C-T

Position:

chr17-4933086-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4BA1

This summary comes from the ClinGen Evidence Repository: The missense variant NM_000173.7(GP1BA):c.482C>T (p.Thr161Met) is associated with the polymorphism HPA-2. Moreover, the Grpmax filtering allele frequency in gnomAD v4.1 is 0.2237 (based on 16982/74950 alleles) in African/African American population, which is significantly higher than the ClinGen PD VCEP threshold (>0.001) for BA1. Additionally, the computational predictor REVEL gives a score of 0.041, which is below the ClinGen PD VCEP threshold of <0.25 predicting no damaging effect on GP1BA function and the SpliceAI score is zero (BP4). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BA1 and BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8314782/MONDO:0009276/079

Frequency

Genomes: 𝑓 0.13 ( 1564 hom., cov: 32)

Exomes 𝑓: 0.084 ( 5913 hom. )

Consequence

GP1BA
NM_000173.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.87

Variant links:

Genes affected

GP1BA (HGNC:4439): (glycoprotein Ib platelet subunit alpha) Glycoprotein Ib (GP Ib) is a platelet surface membrane glycoprotein composed of a heterodimer, an alpha chain and a beta chain, that is linked by disulfide bonds. The Gp Ib functions as a receptor for von Willebrand factor (VWF). The complete receptor complex includes noncovalent association of the alpha and beta subunits with platelet glycoprotein IX and platelet glycoprotein V. The binding of the GP Ib-IX-V complex to VWF facilitates initial platelet adhesion to vascular subendothelium after vascular injury, and also initiates signaling events within the platelet that lead to enhanced platelet activation, thrombosis, and hemostasis. This gene encodes the alpha subunit. Mutations in this gene result in Bernard-Soulier syndromes and platelet-type von Willebrand disease. The coding region of this gene is known to contain a polymophic variable number tandem repeat (VNTR) domain that is associated with susceptibility to nonarteritic anterior ischemic optic neuropathy. [provided by RefSeq, Oct 2013]

GP1BA links:

CHRNE (HGNC:1966): (cholinergic receptor nicotinic epsilon subunit) Acetylcholine receptors at mature mammalian neuromuscular junctions are pentameric protein complexes composed of four subunits in the ratio of two alpha subunits to one beta, one epsilon, and one delta subunit. The acetylcholine receptor changes subunit composition shortly after birth when the epsilon subunit replaces the gamma subunit seen in embryonic receptors. Mutations in the epsilon subunit are associated with congenital myasthenic syndrome. [provided by RefSeq, Sep 2009]

CHRNE links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GP1BA	NM_000173.7 link	c.482C>T	p.Thr161Met	missense_variant	2/2	ENST00000329125.6	NP_000164.5	P07359L7UYB8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GP1BA	ENST00000329125.6 link	c.482C>T	p.Thr161Met	missense_variant	2/2	1	NM_000173.7	ENSP00000329380.5		P07359
CHRNE	ENST00000649830.1 link	c.-888+1256G>A		intron_variant				ENSP00000496907.1		A0A3B3IRM1

Frequencies

GnomAD3 genomes

AF:

0.125

AC:

19005

AN:

152046

Hom.:

1563

Cov.:

show subpopulations

Gnomad AFR

AF:

0.224

Gnomad AMI

AF:

0.0581

Gnomad AMR

AF:

0.135

Gnomad ASJ

AF:

0.130

Gnomad EAS

AF:

0.0599

Gnomad SAS

AF:

0.0592

Gnomad FIN

AF:

0.0877

Gnomad MID

AF:

0.139

Gnomad NFE

AF:

0.0785

Gnomad OTH

AF:

0.129

GnomAD3 exomes

AF:

0.0977

AC:

24317

AN:

249022

Hom.:

1445

AF XY:

0.0938

AC XY:

12681

AN XY:

135164

show subpopulations

Gnomad AFR exome

AF:

0.229

Gnomad AMR exome

AF:

0.138

Gnomad ASJ exome

AF:

0.121

Gnomad EAS exome

AF:

0.0498

Gnomad SAS exome

AF:

0.0600

Gnomad FIN exome

AF:

0.0962

Gnomad NFE exome

AF:

0.0830

Gnomad OTH exome

AF:

0.106

GnomAD4 exome

AF:

0.0840

AC:

122738

AN:

1461638

Hom.:

5913

Cov.:

AF XY:

0.0832

AC XY:

60522

AN XY:

727094

show subpopulations

Gnomad4 AFR exome

AF:

0.230

Gnomad4 AMR exome

AF:

0.137

Gnomad4 ASJ exome

AF:

0.123

Gnomad4 EAS exome

AF:

0.0915

Gnomad4 SAS exome

AF:

0.0626

Gnomad4 FIN exome

AF:

0.0989

Gnomad4 NFE exome

AF:

0.0764

Gnomad4 OTH exome

AF:

0.0900

GnomAD4 genome

AF:

0.125

AC:

19039

AN:

152164

Hom.:

1564

Cov.:

AF XY:

0.125

AC XY:

9332

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.224

Gnomad4 AMR

AF:

0.136

Gnomad4 ASJ

AF:

0.130

Gnomad4 EAS

AF:

0.0600

Gnomad4 SAS

AF:

0.0586

Gnomad4 FIN

AF:

0.0877

Gnomad4 NFE

AF:

0.0785

Gnomad4 OTH

AF:

0.126

Alfa

AF:

0.0910

Hom.:

1813

Bravo

AF:

0.134

TwinsUK

AF:

0.0707

AC:

262

ALSPAC

AF:

0.0828

AC:

319

ESP6500AA

AF:

0.214

AC:

856

ESP6500EA

AF:

0.0796

AC:

663

ExAC

AF:

0.0979

AC:

11832

Asia WGS

AF:

0.0740

AC:

258

AN:

3478

EpiCase

AF:

0.0822

EpiControl

AF:

0.0922

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 11, 2021	This variant is associated with the following publications: (PMID: 12775575, 18417193, 23413192, 15686464) -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.69

CADD

Benign

0.045

DANN

Benign

0.86

DEOGEN2

Benign

0.31

T;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.040

LIST_S2

Benign

0.13

T;T

MetaRNN

Benign

0.0034

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

L;.

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.3

N;.

REVEL

Benign

0.041

Sift

Benign

0.34

T;.

Sift4G

Benign

0.21

T;T

Vest4

0.085

MPC

0.13

ClinPred

0.012

GERP RS

-9.6

Varity_R

0.059

gMVP

0.62

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