17-4932810-C-T

Position:

chr17-4932810-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000173.7(GP1BA):c.206C>T(p.Pro69Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00241 in 1,614,024 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0017 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0025 ( 7 hom. )

Consequence

GP1BA
NM_000173.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: -1.39

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015892774).

BP6

Variant 17-4932810-C-T is Benign according to our data. Variant chr17-4932810-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1285165.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}. Variant chr17-4932810-C-T is described in Lovd as [Benign]. Variant chr17-4932810-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00171 (260/152328) while in subpopulation NFE AF= 0.00301 (205/68026). AF 95% confidence interval is 0.00268. There are 2 homozygotes in gnomad4. There are 120 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GP1BA	NM_000173.7 linkuse as main transcript	c.206C>T	p.Pro69Leu	missense_variant	2/2	ENST00000329125.6	NP_000164.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GP1BA	ENST00000329125.6 linkuse as main transcript	c.206C>T	p.Pro69Leu	missense_variant	2/2	1	NM_000173.7	ENSP00000329380	P1
CHRNE	ENST00000649830.1 linkuse as main transcript	c.-888+1532G>A		intron_variant				ENSP00000496907

Frequencies

GnomAD3 genomes

AF:

0.00171

AC:

260

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000675

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00160

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00301

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00175

AC:

435

AN:

249278

Hom.:

AF XY:

0.00169

AC XY:

229

AN XY:

135228

show subpopulations

Gnomad AFR exome

AF:

0.000323

Gnomad AMR exome

AF:

0.00110

Gnomad ASJ exome

AF:

0.000497

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00158

Gnomad NFE exome

AF:

0.00307

Gnomad OTH exome

AF:

0.000991

GnomAD4 exome

AF:

0.00248

AC:

3626

AN:

1461696

Hom.:

Cov.:

AF XY:

0.00246

AC XY:

1788

AN XY:

727132

show subpopulations

Gnomad4 AFR exome

AF:

0.000448

Gnomad4 AMR exome

AF:

0.000939

Gnomad4 ASJ exome

AF:

0.000689

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00185

Gnomad4 NFE exome

AF:

0.00300

Gnomad4 OTH exome

AF:

0.00190

GnomAD4 genome

AF:

0.00171

AC:

260

AN:

152328

Hom.:

Cov.:

AF XY:

0.00161

AC XY:

120

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.000673

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00160

Gnomad4 NFE

AF:

0.00301

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00242

Hom.:

Bravo

AF:

0.00157

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.000459

AC:

ESP6500EA

AF:

0.00327

AC:

ExAC

AF:

0.00186

AC:

226

EpiCase

AF:

0.00267

EpiControl

AF:

0.00261

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:2

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 06, 2021	DNA sequence analysis of the GP1BA gene demonstrated a sequence change, c.206C>T, in exon 2 that results in an amino acid change, p.Pro69Leu. This sequence change does not appear to have been previously described in individuals with GP1BA-related disorders. This sequence change has been described in the gnomAD database with a low frequency of 0.30% in the non-Finnish European subpopulation (dbSNP rs138825640). The p.Pro69Leu change affects a poorly conserved amino acid residue of the GP1BA protein. The p.Pro69Leu substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to the lack of sufficient evidence, the clinical significance of the p.Pro69Leu change remains unknown at this time. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 16, 2024	Variant summary: GP1BA c.206C>T (p.Pro69Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0017 in 249278 control chromosomes, predominantly at a frequency of 0.0031 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 5 fold of the estimated maximal expected allele frequency for a pathogenic variant in GP1BA causing Bernard Soulier Syndrome phenotype (0.00059). c.206C>T has been reported in the literature in a family with macrothrombocytopenia and Bernard-Soulier syndrome. Both of these publications provided evidence supporting benign effect of this variant (example: Ghevaert_2008 and Bragadottir_2015). The following publications have been ascertained in the context of this evaluation (PMID: 25370924, 18065693, 32757236, 30349881). ClinVar contains an entry for this variant (Variation ID: 1285165). Based on the evidence outlined above, the variant was classified as likely benign. -

Bernard-Soulier syndrome, type A2, autosomal dominant

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

- -

Bernard Soulier syndrome

Uncertain:1

Uncertain significance, no assertion criteria provided

research

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

- -

not provided

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.62

CADD

Benign

0.77

DANN

Benign

0.86

DEOGEN2

Uncertain

0.49

T;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.042

LIST_S2

Benign

0.56

T;T

M_CAP

Benign

0.035

MetaRNN

Benign

0.016

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

L;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.25

PROVEAN

Uncertain

-2.8

D;.

REVEL

Benign

0.030

Sift

Uncertain

0.018

D;.

Sift4G

Benign

0.63

T;T

Vest4

0.19

MVP

0.40

MPC

0.53

ClinPred

0.011

GERP RS

-9.1

Varity_R

0.21

gMVP

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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