17-4933915-A-G

Position:

• chr17-4933915-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000329125.6(GP1BA):​c.1311A>G​(p.Pro437=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (2756 hom., cov: 0)
  • Exomes 𝑓: 0.83 (99379 hom.)
  • Failed GnomAD Quality Control
• Consequence: GP1BA ENST00000329125.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.124

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 17-4933915-A-G is Benign according to our data. Variant chr17-4933915-A-G is described in ClinVar as [Benign]. Clinvar id is 255467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.124 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.755 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GP1BA	NM_000173.7	c.1311A>G	p.Pro437=	synonymous_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.1311A>G	p.Pro437=	synonymous_variant	2/2	1	NM_000173.7	ENSP00000329380	P1
CHRNE	ENST00000649830.1	c.-888+427T>C		intron_variant				ENSP00000496907

Frequencies

GnomAD3 genomes AF: 0.624 AC: 7187 AN: 11514 Hom.: 2746 Cov.: 0

Gnomad AFR AF: 0.778

Gnomad AMI AF: 0.636

Gnomad AMR AF: 0.605

Gnomad ASJ AF: 0.614

Gnomad EAS AF: 0.251

Gnomad SAS AF: 0.321

Gnomad FIN AF: 0.325

Gnomad MID AF: 0.688

Gnomad NFE AF: 0.591

Gnomad OTH AF: 0.580

GnomAD3 exomes AF: 0.369 AC: 37152 AN: 100604 Hom.: 13330 AF XY: 0.389 AC XY: 20825 AN XY: 53530

Gnomad AFR exome AF: 0.316

Gnomad AMR exome AF: 0.367

Gnomad ASJ exome AF: 0.561

Gnomad EAS exome AF: 0.0860

Gnomad SAS exome AF: 0.414

Gnomad FIN exome AF: 0.467

Gnomad NFE exome AF: 0.388

Gnomad OTH exome AF: 0.325

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.828 AC: 242500 AN: 292884 Hom.: 99379 Cov.: 0 AF XY: 0.824 AC XY: 120707 AN XY: 146426

Gnomad4 AFR exome AF: 0.744

Gnomad4 AMR exome AF: 0.784

Gnomad4 ASJ exome AF: 0.761

Gnomad4 EAS exome AF: 0.455

Gnomad4 SAS exome AF: 0.752

Gnomad4 FIN exome AF: 0.670

Gnomad4 NFE exome AF: 0.864

Gnomad4 OTH exome AF: 0.757

GnomAD4 genome AF: 0.625 AC: 7211 AN: 11544 Hom.: 2756 Cov.: 0 AF XY: 0.611 AC XY: 3355 AN XY: 5494

Gnomad4 AFR AF: 0.777

Gnomad4 AMR AF: 0.606

Gnomad4 ASJ AF: 0.614

Gnomad4 EAS AF: 0.251

Gnomad4 SAS AF: 0.326

Gnomad4 FIN AF: 0.325

Gnomad4 NFE AF: 0.591

Gnomad4 OTH AF: 0.575

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 25, 2016	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 14, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.1
DANN	Benign	0.20

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: rs2586529; hg19: chr17-4837210; COSMIC: COSV56698557; COSMIC: COSV56698557;