17-4932775-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PM5 PP3_Strong PP5

The NM_000173.7(GP1BA):c.171C>A(p.Asn57Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N57D) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GP1BA NM_000173.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 1.83

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 Likely_pathogenic. Variant got 9 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-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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 17-4932775-C-A is Pathogenic according to our data. Variant chr17-4932775-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 627016.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GP1BA	NM_000173.7	c.171C>A	p.Asn57Lys	missense_variant	2/2	ENST00000329125.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GP1BA	ENST00000329125.6	c.171C>A	p.Asn57Lys	missense_variant	2/2	1	NM_000173.7	P1
CHRNE	ENST00000649830.1	c.-888+1567G>T		intron_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Macrothrombocytopenia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Feb 01, 2019

- -

GP1BA-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 05, 2024

The GP1BA c.171C>A variant is predicted to result in the amino acid substitution p.Asn57Lys. This variant (aka p.Asn41Lys) has been reported in an individual that was part of a study cohort with platelet number abnormalities, primarily macrothrombocytopenia (Downes et al. 2019. PubMed ID: 31064749. Suppl3_SNV+INDEL). Amino acid residue p.Asn57 is highly conserved and resides in the functional luecine-rich repeat domain of the GP1BA protein. A different substitution of the same amino acid residue, defined as p.Asn57His (aka p.Asn41His) has been reported in association with autosomal dominant Bernard-Soulier syndrome (BSS) in several different families (Berndt and Andrews. 2011. PubMed ID: 21357716; Vettore et al. 2008. PubMed ID: 18815197). 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. We interpret the p.Asn57Lys substitution found in this patient as likely pathogenic. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 27, 2023

Variant summary: GP1BA c.171C>A (p.Asn57Lys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249334 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.171C>A has been reported in the literature in individuals affected platelet disorder (Downes_2019). This report does not provide unequivocal conclusions about association of the variant with Bernard Soulier Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 31064749). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	D;D
Eigen	Uncertain	0.40
Eigen_PC	Benign	0.17
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.70	T;T
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Pathogenic	4.2	H;.
MutationTaster	Benign	0.88	N
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-5.4	D;.
REVEL	Uncertain	0.33
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Vest4		0.90
MutPred		0.76		Loss of catalytic residue at N57 (P = 0.0151);Loss of catalytic residue at N57 (P = 0.0151);
MVP		0.87
MPC		0.58
ClinPred		1.0	D
GERP RS		3.3
Varity_R		0.76
gMVP		0.84

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: rs1597638398; hg19: chr17-4836070;