17-4932696-T-C

Position:

chr17-4932696-T-C

Variant summary

Our verdict is Uncertain significance. Variant got -4 ACMG points: 0P and 4B. BS1

This summary comes from the ClinGen Evidence Repository: The missense variant NM_000173.7(GP1BA):c.92T>C (p.Val31Ala) has been reported in one macrothrombocytopenia patient heterozygous for this variant (PMID:34400424) however the same variant was detected in the mother with normal laboratory parameters. No BSS patients have been reported to our knowledge. The Grpmax Filtering allele frequency in gnomAD v4.1 is 0.0006253 (based on 784/1179792 alleles) in the European (non-Finnish) population, which is higher than the ClinGen PD VCEP threshold (>0.0005; BS1). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BS1 (ClinGen Platelet Disorders VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8314693/MONDO:0009276/079

Frequency

Genomes: 𝑓 0.00074 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00087 ( 6 hom. )

Consequence

GP1BA
NM_000173.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1O:1

Conservation

PhyloP100: 0.219

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 Uncertain_significance. Variant got -4 ACMG points.

BS1

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.92T>C	p.Val31Ala	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.92T>C	p.Val31Ala	missense_variant	2/2	1	NM_000173.7	ENSP00000329380.5		P07359
CHRNE	ENST00000649830.1 link	c.-888+1646A>G		intron_variant				ENSP00000496907.1		A0A3B3IRM1

Frequencies

GnomAD3 genomes

AF:

0.000738

AC:

112

AN:

151762

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000727

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.0179

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000589

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.00125

AC:

312

AN:

249288

Hom.:

AF XY:

0.00129

AC XY:

174

AN XY:

135228

show subpopulations

Gnomad AFR exome

AF:

0.000129

Gnomad AMR exome

AF:

0.000319

Gnomad ASJ exome

AF:

0.0164

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000261

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000991

Gnomad OTH exome

AF:

0.00182

GnomAD4 exome

AF:

0.000874

AC:

1278

AN:

1461698

Hom.:

Cov.:

AF XY:

0.000893

AC XY:

649

AN XY:

727136

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.000335

Gnomad4 ASJ exome

AF:

0.0157

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000139

Gnomad4 FIN exome

AF:

0.000187

Gnomad4 NFE exome

AF:

0.000669

Gnomad4 OTH exome

AF:

0.00128

GnomAD4 genome

AF:

0.000738

AC:

112

AN:

151762

Hom.:

Cov.:

AF XY:

0.000540

AC XY:

AN XY:

74122

show subpopulations

Gnomad4 AFR

AF:

0.0000727

Gnomad4 AMR

AF:

0.000197

Gnomad4 ASJ

AF:

0.0179

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000589

Gnomad4 OTH

AF:

0.00192

Alfa

AF:

0.00158

Hom.:

Bravo

AF:

0.000801

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000937

AC:

ExAC

AF:

0.00111

AC:

134

EpiCase

AF:

0.00169

EpiControl

AF:

0.00184

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Nov 09, 2023

BS1, BS2, PM1 -

Bernard Soulier syndrome;C1280798:Pseudo von Willebrand disease;C3277076:Bernard-Soulier syndrome, type A2, autosomal dominant

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

D;T

Eigen

Benign

0.14

Eigen_PC

Benign

-0.017

FATHMM_MKL

Benign

0.097

LIST_S2

Benign

0.46

T;T

M_CAP

Pathogenic

0.55

MetaRNN

Benign

0.017

T;T

MetaSVM

Pathogenic

0.82

MutationAssessor

Pathogenic

3.0

M;.

PrimateAI

Benign

0.36

PROVEAN

Uncertain

-3.2

D;.

REVEL

Uncertain

0.45

Sift

Uncertain

0.0010

D;.

Sift4G

Uncertain

0.0020

D;D

Vest4

0.16

MVP

0.95

MPC

0.57

ClinPred

0.056

GERP RS

3.3

Varity_R

0.61

gMVP

0.54

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