17-4933086-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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 reviewed by expert panel B:4

Conservation

PhyloP100: -1.87

Publications

111 publications found

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 Gene-Disease associations (from GenCC):

congenital myasthenic syndrome
Inheritance: AR Classification: DEFINITIVE Submitted by: Illumina
congenital myasthenic syndrome 4A
Inheritance: AD, AR Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia
congenital myasthenic syndrome 4B
Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia
congenital myasthenic syndrome 4C
Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
postsynaptic congenital myasthenic syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CHRNE links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
GP1BA	NM_000173.7 link	c.482C>T	p.Thr161Met	missense_variant	Exon 2 of 2	ENST00000329125.6	NP_000164.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GP1BA	ENST00000329125.6 link	c.482C>T	p.Thr161Met	missense_variant	Exon 2 of 2	1	NM_000173.7	ENSP00000329380.5
CHRNE	ENST00000649830.1 link	c.-888+1256G>A		intron_variant	Intron 1 of 10			ENSP00000496907.1

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

GnomAD2 exomes

AF:

0.0977

AC:

24317

AN:

249022

AF XY:

0.0938

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 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

African (AFR)

AF:

0.230

AC:

7695

AN:

33478

American (AMR)

AF:

0.137

AC:

6148

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.123

AC:

3202

AN:

26136

East Asian (EAS)

AF:

0.0915

AC:

3633

AN:

39700

South Asian (SAS)

AF:

0.0626

AC:

5400

AN:

86258

European-Finnish (FIN)

AF:

0.0989

AC:

5283

AN:

53396

Middle Eastern (MID)

AF:

0.177

AC:

1020

AN:

5766

European-Non Finnish (NFE)

AF:

0.0764

AC:

84921

AN:

1111810

Other (OTH)

AF:

0.0900

AC:

5436

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

6592

13185

19777

26370

32962

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3266

6532

9798

13064

16330

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.125

AC:

19039

AN:

152164

Hom.:

1564

Cov.:

AF XY:

0.125

AC XY:

9332

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.224

AC:

9287

AN:

41472

American (AMR)

AF:

0.136

AC:

2074

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.130

AC:

452

AN:

3470

East Asian (EAS)

AF:

0.0600

AC:

311

AN:

5180

South Asian (SAS)

AF:

0.0586

AC:

283

AN:

4828

European-Finnish (FIN)

AF:

0.0877

AC:

931

AN:

10610

Middle Eastern (MID)

AF:

0.150

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0785

AC:

5338

AN:

68004

Other (OTH)

AF:

0.126

AC:

266

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

840

1680

2520

3360

4200

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

186

372

558

744

930

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0977

Hom.:

4042

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:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 11, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 12775575, 18417193, 23413192, 15686464) -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Bernard Soulier syndrome

Benign:1

Feb 11, 2025

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

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. -

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

(source)

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;.

PhyloP100

-1.9

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

Mutation Taster

=87/13

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over