rs121908065

Positions:

• chr17-4933119-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PP5_Very_Strong

The NM_000173.7(GP1BA):​c.515C>T​(p.Ala172Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,550 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GP1BA NM_000173.7 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 0.982

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]

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a repeat LRR 6 (size 21) in uniprot entity GP1BA_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000173.7
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-4933119-C-T is Pathogenic according to our data. Variant chr17-4933119-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 4156.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4933119-C-T is described in Lovd as [Pathogenic]. Variant chr17-4933119-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GP1BA	NM_000173.7	c.515C>T	p.Ala172Val	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	c.515C>T	p.Ala172Val	missense_variant	2/2	1	NM_000173.7	ENSP00000329380.5
CHRNE	ENST00000649830.1	c.-888+1223G>A		intron_variant				ENSP00000496907.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461550 Hom.: 0 Cov.: 38 AF XY: 0.00000275 AC XY: 2 AN XY: 727064

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bernard-Soulier syndrome, type A2, autosomal dominant Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2001	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 19, 2023	Variant summary: GP1BA c.515C>T (p.Ala172Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249014 control chromosomes (gnomAD). c.515C>T has been reported in the literature in numerous heterozygous individuals affected with Bernard-Soulier Syndrome, Type A2, Autosomal Dominant, and the variant has been shown to segregate with disease in related individuals (e.g., Savoia_2001, Noris_2012). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 21933849, 11222377). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -

Bernard-Soulier syndrome, type A1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2001

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 25, 2023

Experimental studies have shown that this missense change affects GP1BA function (PMID: 1694864, 7690774, 11222377, 19067792). For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GP1BA protein function. ClinVar contains an entry for this variant (Variation ID: 4156). This variant is also known as Bolzano mutation, Ala156Val. This missense change has been observed in individuals with the classical form of autosomal recessive Bernard-Soulier syndrome. It has also been reported in a heterozygous state with autosomal dominant macrothrombocytopenia in many families and has been considered as the most frequent cause of inherited thrombocytopenia in Italy (PMID: 7690774, 10235425, 11222377, 19067792, 21933849). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 172 of the GP1BA protein (p.Ala172Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T;T
Eigen	Benign	0.16
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.75	T;T
M_CAP	Benign	0.058	D
MetaRNN	Uncertain	0.60	D;D
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	1.3	L;.
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.0	D;.
REVEL	Uncertain	0.36
Sift	Uncertain	0.0090	D;.
Sift4G	Uncertain	0.0090	D;D
Vest4		0.33
MutPred		0.70		Loss of disorder (P = 0.1431);Loss of disorder (P = 0.1431);
MVP		0.88
MPC		0.52
ClinPred		0.95	D
GERP RS		4.8
Varity_R		0.84
gMVP		0.79

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

Other links and lift over

dbSNP: rs121908065; hg19: chr17-4836414;