rs770089708

chr17-4933925-TCAGAGCCCGCCCCCAGCCCGACC-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 4P and 16B. PVS1_Strong BP6_Very_Strong BA1

The NM_000173.7(GP1BA):c.1322_1344del(p.Ser441TyrfsTer49) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.405 in 27,426 control chromosomes in the GnomAD database, including 859 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (859 hom., cov: 0)
  • Exomes 𝑓: 0.15 (4834 hom.)
  • Failed GnomAD Quality Control
• Consequence: GP1BA NM_000173.7 frameshift
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.20

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 -12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 11 pathogenic variants in the truncated region.
• BP6: Variant 17-4933925-TCAGAGCCCGCCCCCAGCCCGACC-T is Benign according to our data. Variant chr17-4933925-TCAGAGCCCGCCCCCAGCCCGACC-T is described in ClinVar as [Likely_benign]. Clinvar id is 435346.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.467 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GP1BA	NM_000173.7	c.1322_1344del	p.Ser441TyrfsTer49	frameshift_variant	2/2	ENST00000329125.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GP1BA	ENST00000329125.6	c.1322_1344del	p.Ser441TyrfsTer49	frameshift_variant	2/2	1	NM_000173.7	P1
CHRNE	ENST00000649830.1	c.-888+394_-888+416del		intron_variant

Frequencies

GnomAD3 genomes AF: 0.405 AC: 11099 AN: 27408 Hom.: 859 Cov.: 0

Gnomad AFR AF: 0.294

Gnomad AMI AF: 0.495

Gnomad AMR AF: 0.436

Gnomad ASJ AF: 0.330

Gnomad EAS AF: 0.379

Gnomad SAS AF: 0.494

Gnomad FIN AF: 0.388

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.433

Gnomad OTH AF: 0.387

GnomAD3 exomes AF: 0.109 AC: 9489 AN: 87154 Hom.: 903 AF XY: 0.100 AC XY: 4957 AN XY: 49398

Gnomad AFR exome AF: 0.165

Gnomad AMR exome AF: 0.169

Gnomad ASJ exome AF: 0.0223

Gnomad EAS exome AF: 0.253

Gnomad SAS exome AF: 0.124

Gnomad FIN exome AF: 0.0376

Gnomad NFE exome AF: 0.0930

Gnomad OTH exome AF: 0.138

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.146 AC: 60871 AN: 417474 Hom.: 4834 AF XY: 0.153 AC XY: 34026 AN XY: 221674

Gnomad4 AFR exome AF: 0.0908

Gnomad4 AMR exome AF: 0.153

Gnomad4 ASJ exome AF: 0.0812

Gnomad4 EAS exome AF: 0.238

Gnomad4 SAS exome AF: 0.245

Gnomad4 FIN exome AF: 0.128

Gnomad4 NFE exome AF: 0.124

Gnomad4 OTH exome AF: 0.169

GnomAD4 genome AF: 0.405 AC: 11102 AN: 27426 Hom.: 859 Cov.: 0 AF XY: 0.396 AC XY: 5271 AN XY: 13326

Gnomad4 AFR AF: 0.293

Gnomad4 AMR AF: 0.435

Gnomad4 ASJ AF: 0.330

Gnomad4 EAS AF: 0.380

Gnomad4 SAS AF: 0.495

Gnomad4 FIN AF: 0.388

Gnomad4 NFE AF: 0.433

Gnomad4 OTH AF: 0.393

Alfa AF: 0.0460 Hom.: 17

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 16, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 04, 2021

- -

Bernard Soulier syndrome;C1280798:Pseudo von Willebrand disease;C1847711:Nonarteritic anterior ischemic optic neuropathy, susceptibility to;C3277076:Bernard-Soulier syndrome, type A2, autosomal dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 03, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs770089708; hg19: chr17-4837220; COSMIC: COSV99851242; COSMIC: COSV99851242;