rs6067

Positions:

• chr17-4933678-A-G
• chr17-4933678-A-T

Variant summary

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

The NM_000173.7(GP1BA):​c.1074A>G​(p.Arg358=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0455 in 1,613,836 control chromosomes in the GnomAD database, including 2,978 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.049 (318 hom., cov: 31)
  • Exomes 𝑓: 0.045 (2660 hom.)
• Consequence: GP1BA NM_000173.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.334

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 17-4933678-A-G is Benign according to our data. Variant chr17-4933678-A-G is described in ClinVar as [Benign]. Clinvar id is 255463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4933678-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.334 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.204 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GP1BA	NM_000173.7	c.1074A>G	p.Arg358=	synonymous_variant	2/2	ENST00000329125.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GP1BA	ENST00000329125.6	c.1074A>G	p.Arg358=	synonymous_variant	2/2	1	NM_000173.7	P1
CHRNE	ENST00000649830.1	c.-888+664T>C		intron_variant

Frequencies

GnomAD3 genomes AF: 0.0487 AC: 7400 AN: 152040 Hom.: 318 Cov.: 31

Gnomad AFR AF: 0.0265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.121

Gnomad ASJ AF: 0.0484

Gnomad EAS AF: 0.215

Gnomad SAS AF: 0.0952

Gnomad FIN AF: 0.0240

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0344

Gnomad OTH AF: 0.0517

GnomAD3 exomes AF: 0.0692 AC: 17253 AN: 249270 Hom.: 993 AF XY: 0.0669 AC XY: 9047 AN XY: 135228

Gnomad AFR exome AF: 0.0278

Gnomad AMR exome AF: 0.138

Gnomad ASJ exome AF: 0.0575

Gnomad EAS exome AF: 0.214

Gnomad SAS exome AF: 0.0914

Gnomad FIN exome AF: 0.0255

Gnomad NFE exome AF: 0.0345

Gnomad OTH exome AF: 0.0638

GnomAD4 exome AF: 0.0452 AC: 66052 AN: 1461678 Hom.: 2660 Cov.: 38 AF XY: 0.0465 AC XY: 33793 AN XY: 727122

Gnomad4 AFR exome AF: 0.0269

Gnomad4 AMR exome AF: 0.135

Gnomad4 ASJ exome AF: 0.0565

Gnomad4 EAS exome AF: 0.215

Gnomad4 SAS exome AF: 0.0925

Gnomad4 FIN exome AF: 0.0267

Gnomad4 NFE exome AF: 0.0323

Gnomad4 OTH exome AF: 0.0559

GnomAD4 genome AF: 0.0486 AC: 7401 AN: 152158 Hom.: 318 Cov.: 31 AF XY: 0.0516 AC XY: 3836 AN XY: 74382

Gnomad4 AFR AF: 0.0265

Gnomad4 AMR AF: 0.122

Gnomad4 ASJ AF: 0.0484

Gnomad4 EAS AF: 0.214

Gnomad4 SAS AF: 0.0942

Gnomad4 FIN AF: 0.0240

Gnomad4 NFE AF: 0.0344

Gnomad4 OTH AF: 0.0502

Alfa AF: 0.0380 Hom.: 62

Bravo AF: 0.0552

Asia WGS AF: 0.128 AC: 444 AN: 3478

EpiCase AF: 0.0374

EpiControl AF: 0.0373

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.9
DANN	Benign	0.77

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: rs6067; hg19: chr17-4836973; COSMIC: COSV56699556; COSMIC: COSV56699556;