rs758041497

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 4P and 16B. PVS1_StrongBP6_Very_StrongBA1

The NM_000173.7(GP1BA):c.1305_1320delCACCCCAGAGCCCACC(p.Thr436GlnfsTer31) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. 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

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.945

Publications

0 publications found

Variant links:

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]

GP1BA links:

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

CHRNE links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 16 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 rank	MANE	Protein	UniProt
GP1BA	NM_000173.7 link	c.1305_1320delCACCCCAGAGCCCACC	p.Thr436GlnfsTer31	frameshift_variant	Exon 2 of 2	ENST00000329125.6	NP_000164.5	P07359L7UYB8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GP1BA	ENST00000329125.6 link	c.1305_1320delCACCCCAGAGCCCACC	p.Thr436GlnfsTer31	frameshift_variant	Exon 2 of 2	1	NM_000173.7	ENSP00000329380.5		P07359
CHRNE	ENST00000649830.1 link	c.-888+419_-888+434delGTGGGCTCTGGGGTGG		intron_variant	Intron 1 of 10			ENSP00000496907.1		A0A3B3IRM1

Frequencies

GnomAD3 genomes

AF:

0.308

AC:

10508

AN:

34096

Hom.:

965

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0706

AC:

9463

AN:

133946

AF XY:

0.0679

show subpopulations

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 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

show subpopulations

African (AFR)

AF:

0.0719

AC:

706

AN:

9820

American (AMR)

AF:

0.127

AC:

2489

AN:

19594

Ashkenazi Jewish (ASJ)

AF:

0.102

AC:

988

AN:

9650

East Asian (EAS)

AF:

0.430

AC:

5038

AN:

11712

South Asian (SAS)

AF:

0.300

AC:

12303

AN:

40950

European-Finnish (FIN)

AF:

0.238

AC:

3352

AN:

14090

Middle Eastern (MID)

AF:

0.135

AC:

198

AN:

1466

European-Non Finnish (NFE)

AF:

0.103

AC:

32708

AN:

318058

Other (OTH)

AF:

0.190

AC:

3380

AN:

17806

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.526

Heterozygous variant carriers

2239

4477

6716

8954

11193

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.308

AC:

10511

AN:

34110

Hom.:

965

Cov.:

AF XY:

0.303

AC XY:

4924

AN XY:

16272

show subpopulations

African (AFR)

AF:

0.158

AC:

1253

AN:

7950

American (AMR)

AF:

0.336

AC:

1123

AN:

3344

Ashkenazi Jewish (ASJ)

AF:

0.253

AC:

188

AN:

744

East Asian (EAS)

AF:

0.315

AC:

649

AN:

2058

South Asian (SAS)

AF:

0.466

AC:

805

AN:

1726

European-Finnish (FIN)

AF:

0.278

AC:

527

AN:

1898

Middle Eastern (MID)

AF:

0.278

AC:

AN:

European-Non Finnish (NFE)

AF:

0.365

AC:

5733

AN:

15700

Other (OTH)

AF:

0.294

AC:

123

AN:

418

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.572

Heterozygous variant carriers

355

710

1065

1420

1775

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Oct 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 04, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Aug 16, 2016

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.94

Mutation Taster

=37/163

polymorphism (auto)

(source)

Splicing

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

Publications

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rs758041497

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over