17-4932773-A-G

Position:

• chr17-4932773-A-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000173.7(GP1BA):​c.169A>G​(p.Asn57Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N57H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GP1BA NM_000173.7 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 4.70

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 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-4932773-A-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 17-4932773-A-G is Pathogenic according to our data. Variant chr17-4932773-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1676741.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GP1BA	NM_000173.7	c.169A>G	p.Asn57Asp	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.169A>G	p.Asn57Asp	missense_variant	2/2	1	NM_000173.7	ENSP00000329380	P1
CHRNE	ENST00000649830.1	c.-888+1569T>C		intron_variant				ENSP00000496907

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bernard-Soulier syndrome, type A2, autosomal dominant Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

-

- -

GP1BA-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 01, 2023

The GP1BA c.169A>G variant is predicted to result in the amino acid substitution p.Asn57Asp. This variant has been reported in the heterozygous state in an individual with Bernard-Soulier syndrome (Table S2, Megy et al. 2021. PubMed ID: 34355501). This variant has also been reported in the heterozygous state in an individual with thrombocytopenia (Marconi et al. 2022. PubMed ID: 36519321). A different substitution of the same amino acid residue defined as p.Asn57His was reported in a patient with Bernard-Soulier syndrome (BSS) (legacy nomenclature N41H, Berndt and Andrews. 2011. PubMed ID: 21357716). The p.Asn57His substitution was also reported in the heterozygous state in two families with Bernard-Soulier syndrome and functional studies suggest this variant alters a region of the GP1BA protein required for VWF binding (Vettore et al. 2008. PubMed ID: 18815197). Another variant of the same amino acid residue, defined as p.Asn57Lys, is reported as likely pathogenic in ClinVar and is reported in the heterozygous state in a patient with a platelet-related bleeding disorder (suppl3, Downes et al. 2019. PubMed ID: 31064749). These data suggest that substitution of amino acid residue p.Asn57 is not tolerated. This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. In Clinvar, this variant is interpreted as like pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/1676741/). This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.044	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.84	D;D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.68	T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Pathogenic	4.7	H;.
MutationTaster	Benign	0.65	N
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-4.5	D;.
REVEL	Uncertain	0.37
Sift	Uncertain	0.0010	D;.
Sift4G	Pathogenic	0.0	D;D
Vest4		0.91
MutPred		0.74		Gain of sheet (P = 0.1451);Gain of sheet (P = 0.1451);
MVP		0.87
MPC		0.54
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.91
gMVP		0.81

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-4836068;