rs6066

chr17-4933378-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000173.7(GP1BA):c.774C>T(p.Asn258=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0316 in 1,613,822 control chromosomes in the GnomAD database, including 1,000 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (62 hom., cov: 31)
  • Exomes 𝑓: 0.033 (938 hom.)
• Consequence: GP1BA NM_000173.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.46

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 17-4933378-C-T is Benign according to our data. Variant chr17-4933378-C-T is described in ClinVar as [Benign]. Clinvar id is 255469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4933378-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.46 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0221 (3366/152258) while in subpopulation NFE AF= 0.0346 (2355/68010). AF 95% confidence interval is 0.0335. There are 62 homozygotes in gnomad4. There are 1545 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 62 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GP1BA	NM_000173.7	c.774C>T	p.Asn258=	synonymous_variant	2/2	ENST00000329125.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GP1BA	ENST00000329125.6	c.774C>T	p.Asn258=	synonymous_variant	2/2	1	NM_000173.7	P1
CHRNE	ENST00000649830.1	c.-888+964G>A		intron_variant

Frequencies

GnomAD3 genomes AF: 0.0221 AC: 3366 AN: 152140 Hom.: 62 Cov.: 31

Gnomad AFR AF: 0.00814

Gnomad AMI AF: 0.0658

Gnomad AMR AF: 0.0238

Gnomad ASJ AF: 0.0184

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.0108

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0346

Gnomad OTH AF: 0.0258

GnomAD3 exomes AF: 0.0218 AC: 5446 AN: 249270 Hom.: 80 AF XY: 0.0220 AC XY: 2977 AN XY: 135226

Gnomad AFR exome AF: 0.00555

Gnomad AMR exome AF: 0.0176

Gnomad ASJ exome AF: 0.0167

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00366

Gnomad FIN exome AF: 0.0145

Gnomad NFE exome AF: 0.0357

Gnomad OTH exome AF: 0.0198

GnomAD4 exome AF: 0.0326 AC: 47644 AN: 1461564 Hom.: 938 Cov.: 38 AF XY: 0.0314 AC XY: 22828 AN XY: 727070

Gnomad4 AFR exome AF: 0.00511

Gnomad4 AMR exome AF: 0.0180

Gnomad4 ASJ exome AF: 0.0179

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00410

Gnomad4 FIN exome AF: 0.0143

Gnomad4 NFE exome AF: 0.0391

Gnomad4 OTH exome AF: 0.0264

GnomAD4 genome AF: 0.0221 AC: 3366 AN: 152258 Hom.: 62 Cov.: 31 AF XY: 0.0208 AC XY: 1545 AN XY: 74450

Gnomad4 AFR AF: 0.00812

Gnomad4 AMR AF: 0.0238

Gnomad4 ASJ AF: 0.0184

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00331

Gnomad4 FIN AF: 0.0108

Gnomad4 NFE AF: 0.0346

Gnomad4 OTH AF: 0.0256

Alfa AF: 0.0326 Hom.: 98

Bravo AF: 0.0226

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0327

EpiControl AF: 0.0331

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

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- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jul 30, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.14
Dann	Benign	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: rs6066; hg19: chr17-4836673;