rs758041497

Positions:

• chr17-4933907-ACCACCCCAGAGCCCAC-A

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.1305_1320del​(p.Thr436GlnfsTer31) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T435T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.31 (965 hom., cov: 0)
  • Exomes 𝑓: 0.14 (4827 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: 0.945

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 17-4933907-ACCACCCCAGAGCCCAC-A is Benign according to our data. Variant chr17-4933907-ACCACCCCAGAGCCCAC-A is described in ClinVar as [Likely_benign]. Clinvar id is 435345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.44 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GP1BA	NM_000173.7	c.1305_1320del	p.Thr436GlnfsTer31	frameshift_variant	2/2	ENST00000329125.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GP1BA	ENST00000329125.6	c.1305_1320del	p.Thr436GlnfsTer31	frameshift_variant	2/2	1	NM_000173.7	P1
CHRNE	ENST00000649830.1	c.-888+419_-888+434del		intron_variant

Frequencies

GnomAD3 genomes AF: 0.308 AC: 10508 AN: 34096 Hom.: 965 Cov.: 0

Gnomad AFR AF: 0.158

Gnomad AMI AF: 0.436

Gnomad AMR AF: 0.337

Gnomad ASJ AF: 0.253

Gnomad EAS AF: 0.315

Gnomad SAS AF: 0.464

Gnomad FIN AF: 0.278

Gnomad MID AF: 0.293

Gnomad NFE AF: 0.365

Gnomad OTH AF: 0.286

GnomAD3 exomes AF: 0.0706 AC: 9463 AN: 133946 Hom.: 909 AF XY: 0.0679 AC XY: 4952 AN XY: 72910

Gnomad AFR exome AF: 0.0440

Gnomad AMR exome AF: 0.0653

Gnomad ASJ exome AF: 0.0162

Gnomad EAS exome AF: 0.142

Gnomad SAS exome AF: 0.103

Gnomad FIN exome AF: 0.0409

Gnomad NFE exome AF: 0.0617

Gnomad OTH exome AF: 0.0779

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.138 AC: 61162 AN: 443146 Hom.: 4827 AF XY: 0.152 AC XY: 34213 AN XY: 225518

Gnomad4 AFR exome AF: 0.0719

Gnomad4 AMR exome AF: 0.127

Gnomad4 ASJ exome AF: 0.102

Gnomad4 EAS exome AF: 0.430

Gnomad4 SAS exome AF: 0.300

Gnomad4 FIN exome AF: 0.238

Gnomad4 NFE exome AF: 0.103

Gnomad4 OTH exome AF: 0.190

GnomAD4 genome AF: 0.308 AC: 10511 AN: 34110 Hom.: 965 Cov.: 0 AF XY: 0.303 AC XY: 4924 AN XY: 16272

Gnomad4 AFR AF: 0.158

Gnomad4 AMR AF: 0.336

Gnomad4 ASJ AF: 0.253

Gnomad4 EAS AF: 0.315

Gnomad4 SAS AF: 0.466

Gnomad4 FIN AF: 0.278

Gnomad4 NFE AF: 0.365

Gnomad4 OTH AF: 0.294

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jul 06, 2023	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 16, 2016

- -

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: rs758041497; hg19: chr17-4837202;