17-4932557-A-T

Variant names:

• chr17-4932557-A-T
• rs81663
• NM_000173.7:c.-6-42A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000173.7(GP1BA):​c.-6-42A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.343 in 1,536,438 control chromosomes in the GnomAD database, including 95,223 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6421 hom., cov: 27)
  • Exomes 𝑓: 0.35 (88802 hom.)
• Consequence: GP1BA NM_000173.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.932
• Publications: 10 publications found

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]

CHRNE Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: Illumina
• congenital myasthenic syndrome 4A

  Inheritance: AD, AR Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia
• congenital myasthenic syndrome 4B

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia
• congenital myasthenic syndrome 4C

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• postsynaptic congenital myasthenic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 17-4932557-A-T is Benign according to our data. Variant chr17-4932557-A-T is described in ClinVar as [Benign]. Clinvar id is 1224607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.369 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GP1BA	NM_000173.7	c.-6-42A>T		intron_variant	Intron 1 of 1	ENST00000329125.6	NP_000164.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GP1BA	ENST00000329125.6	c.-6-42A>T		intron_variant	Intron 1 of 1	1	NM_000173.7	ENSP00000329380.5
CHRNE	ENST00000649830.1	c.-888+1785T>A		intron_variant	Intron 1 of 10			ENSP00000496907.1

Frequencies

GnomAD3 genomes AF: 0.266 AC: 39042 AN: 146584 Hom.: 6419 Cov.: 27

Gnomad AFR AF: 0.0724

Gnomad AMI AF: 0.241

Gnomad AMR AF: 0.331

Gnomad ASJ AF: 0.319

Gnomad EAS AF: 0.114

Gnomad SAS AF: 0.193

Gnomad FIN AF: 0.319

Gnomad MID AF: 0.224

Gnomad NFE AF: 0.373

Gnomad OTH AF: 0.294

GnomAD2 exomes AF: 0.298 AC: 66238 AN: 222086 AF XY: 0.299

Gnomad AFR exome AF: 0.0612

Gnomad AMR exome AF: 0.375

Gnomad ASJ exome AF: 0.311

Gnomad EAS exome AF: 0.112

Gnomad FIN exome AF: 0.306

Gnomad NFE exome AF: 0.368

Gnomad OTH exome AF: 0.310

GnomAD4 exome AF: 0.351 AC: 488339 AN: 1389726 Hom.: 88802 Cov.: 28 AF XY: 0.347 AC XY: 238342 AN XY: 687782

African (AFR) AF: 0.0557 AC: 1749 AN: 31418

American (AMR) AF: 0.369 AC: 15724 AN: 42556

Ashkenazi Jewish (ASJ) AF: 0.322 AC: 7541 AN: 23390

East Asian (EAS) AF: 0.0941 AC: 3650 AN: 38780

South Asian (SAS) AF: 0.191 AC: 15255 AN: 79910

European-Finnish (FIN) AF: 0.314 AC: 16162 AN: 51538

Middle Eastern (MID) AF: 0.262 AC: 1377 AN: 5260

European-Non Finnish (NFE) AF: 0.385 AC: 408424 AN: 1059542

Other (OTH) AF: 0.322 AC: 18457 AN: 57332

GnomAD4 genome AF: 0.266 AC: 39073 AN: 146712 Hom.: 6421 Cov.: 27 AF XY: 0.262 AC XY: 18678 AN XY: 71412

African (AFR) AF: 0.0722 AC: 2894 AN: 40088

American (AMR) AF: 0.330 AC: 4904 AN: 14840

Ashkenazi Jewish (ASJ) AF: 0.319 AC: 1086 AN: 3404

East Asian (EAS) AF: 0.115 AC: 525 AN: 4580

South Asian (SAS) AF: 0.195 AC: 854 AN: 4378

European-Finnish (FIN) AF: 0.319 AC: 3073 AN: 9644

Middle Eastern (MID) AF: 0.234 AC: 68 AN: 290

European-Non Finnish (NFE) AF: 0.373 AC: 24845 AN: 66550

Other (OTH) AF: 0.298 AC: 608 AN: 2040

Alfa AF: 0.314 Hom.: 1537

Bravo AF: 0.261

Asia WGS AF: 0.162 AC: 561 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 12, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.0
DANN	Benign	0.72
PhyloP100		-0.93
PromoterAI		0.013	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs81663; hg19: chr17-4835852; COSMIC: COSV56701192; COSMIC: COSV56701192;