rs1259394995

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM4BP6_Very_Strong

The NM_000173.7(GP1BA):c.1321_1359delTCAGAGCCCGCCCCCAGCCCGACCACCCCGGAGCCCACC(p.Ser441_Thr453del) variant causes a conservative inframe deletion 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 (★★).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000026 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GP1BA
NM_000173.7 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.745

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: Likely_benign. The variant received -6 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_000173.7.

BP6

Variant 17-4933915-AGAGCCCACCTCAGAGCCCGCCCCCAGCCCGACCACCCCG-A is Benign according to our data. Variant chr17-4933915-AGAGCCCACCTCAGAGCCCGCCCCCAGCCCGACCACCCCG-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255468.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GP1BA	NM_000173.7 link	c.1321_1359delTCAGAGCCCGCCCCCAGCCCGACCACCCCGGAGCCCACC	p.Ser441_Thr453del	conservative_inframe_deletion	Exon 2 of 2	ENST00000329125.6	NP_000164.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GP1BA	ENST00000329125.6 link	c.1321_1359delTCAGAGCCCGCCCCCAGCCCGACCACCCCGGAGCCCACC	p.Ser441_Thr453del	conservative_inframe_deletion	Exon 2 of 2	1	NM_000173.7	ENSP00000329380.5
CHRNE	ENST00000649830.1 link	c.-888+388_-888+426delCGGGGTGGTCGGGCTGGGGGCGGGCTCTGAGGTGGGCTC		intron_variant	Intron 1 of 10			ENSP00000496907.1

Frequencies

GnomAD3 genomes

AF:

0.000169

AC:

AN:

11854

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000859

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000244

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000260

AC:

AN:

308274

Hom.:

AF XY:

0.0000259

AC XY:

AN XY:

154716

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

11022

American (AMR)

AF:

0.00

AC:

AN:

15564

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

9284

East Asian (EAS)

AF:

0.000188

AC:

AN:

5308

South Asian (SAS)

AF:

0.0000511

AC:

AN:

19586

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10784

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1260

European-Non Finnish (NFE)

AF:

0.0000180

AC:

AN:

222576

Other (OTH)

AF:

0.000155

AC:

AN:

12890

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.681

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000169

AC:

AN:

11854

Hom.:

Cov.:

AF XY:

0.000177

AC XY:

AN XY:

5652

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

4446

American (AMR)

AF:

0.000859

AC:

AN:

1164

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

308

East Asian (EAS)

AF:

0.00

AC:

AN:

580

South Asian (SAS)

AF:

0.00

AC:

AN:

370

European-Finnish (FIN)

AF:

0.00

AC:

AN:

652

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000244

AC:

AN:

4092

Other (OTH)

AF:

0.00

AC:

AN:

162

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.600

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 25, 2016

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.74

Mutation Taster

=178/22

polymorphism

(source)

Splicing

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

Publications

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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