rs121908063

Positions:

• chr17-4932821-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The ENST00000329125.6(GP1BA):​c.217C>T​(p.Leu73Phe) 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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GP1BA ENST00000329125.6 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.56

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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 17-4932821-C-T is Pathogenic according to our data. Variant chr17-4932821-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4932821-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.217C>T	p.Leu73Phe	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.217C>T	p.Leu73Phe	missense_variant	2/2	1	NM_000173.7	ENSP00000329380	P1
CHRNE	ENST00000649830.1	c.-888+1521G>A		intron_variant				ENSP00000496907

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bernard-Soulier syndrome, type A2, autosomal dominant Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 15, 1992	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 11, 2024	Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Likely pathogenic. Following criteria are met: 0103 - Gain of function and loss of function are known mechanisms of disease in this gene. The former is associated with autosomal dominant von Willebrand disease, platelet-type (MIM#177820), whereas the latter is associated with autosomal recessive Bernard-Soulier syndrome, type A1 (MIM#231200) and autosomal dominant Bernard-Soulier syndrome, type A2 (MIM#153670) (ClinGen). In addition, dominant negative is a suggested mechanism for autosomal dominant Bernard-Soulier syndrome, type A2 (MIM#153670) (PMID: 24934643). (I) 0108 - This gene is associated with both recessive and dominant disease. Autosomal dominant Bernard-Soulier syndrome, type A2 (MIM#153670) is rare and milder than autosomal recessive Bernard-Soulier syndrome, type A1 (MIM#231200). In addition, majority of the variants implicated in von Willebrand disease, platelet-type (MIM#177820) are located within the beta-hairpin loop (PMIDs: 24934643, 37592722). (I) 0200 - Variant is predicted to result in a missense amino acid change from leucine to phenylalanine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (v2, v3 and v4). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated leucine-rich repeat (LRR) region (PMIDs: 33732333, 36173017). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported in the heterozygous state in multiple individuals, including a family exhibiting a Bernard-Soulier disease phenotype (PMIDs: 1730088, 31064749, 36507135, 36173017). (SP) 0903 - This variant has limited evidence for segregation with disease. This variant was identified in the heterozygous state in three individuals from one family with Bernard-Soulier syndrome, and was absent in at least one unaffected family member. Segregation of this variant in the family was determined via an allele-specific hybridisation assay (PMID: 1730088). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Macrothrombocytopenia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Feb 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D;D
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.54	T;T
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Pathogenic	4.4	H;.
MutationTaster	Benign	0.50	A
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.1	D;.
REVEL	Uncertain	0.61
Sift	Uncertain	0.014	D;.
Sift4G	Pathogenic	0.0	D;D
Vest4		0.87
MutPred		0.89		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.93
MPC		0.56
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.51
gMVP		0.81

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

Other links and lift over

dbSNP: rs121908063; hg19: chr17-4836116;