17-4933822-AAGCCCGACCACCCCAGAGCCCACCTCAGAGCCCGCCCCCAGCCCGACCACCCCGGAGCCCACCTCAGAGCCCGCCCCC-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PM4BP6_Very_StrongBA1

The NM_000173.7(GP1BA):c.1282_1359delTCAGAGCCCGCCCCCAGCCCGACCACCCCAGAGCCCACCTCAGAGCCCGCCCCCAGCCCGACCACCCCGGAGCCCACC(p.Ser428_Thr453del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0168 in 144,606 control chromosomes in the GnomAD database, including 72 homozygotes. 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 0.017 ( 72 hom., cov: 26)

Exomes 𝑓: 0.026 ( 1927 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:3

Conservation

PhyloP100: 0.807

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 -14 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_000173.7.

BP6

Variant 17-4933822-AAGCCCGACCACCCCAGAGCCCACCTCAGAGCCCGCCCCCAGCCCGACCACCCCGGAGCCCACCTCAGAGCCCGCCCCC-A is Benign according to our data. Variant chr17-4933822-AAGCCCGACCACCCCAGAGCCCACCTCAGAGCCCGCCCCCAGCCCGACCACCCCGGAGCCCACCTCAGAGCCCGCCCCC-A is described in ClinVar as [Likely_benign]. Clinvar id is 435348.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.058 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GP1BA	NM_000173.7 link	c.1282_1359delTCAGAGCCCGCCCCCAGCCCGACCACCCCAGAGCCCACCTCAGAGCCCGCCCCCAGCCCGACCACCCCGGAGCCCACC	p.Ser428_Thr453del	conservative_inframe_deletion	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.1282_1359delTCAGAGCCCGCCCCCAGCCCGACCACCCCAGAGCCCACCTCAGAGCCCGCCCCCAGCCCGACCACCCCGGAGCCCACC	p.Ser428_Thr453del	conservative_inframe_deletion	Exon 2 of 2	1	NM_000173.7	ENSP00000329380.5		P07359
CHRNE	ENST00000649830.1 link	c.-888+442_-888+519delGGGGGCGGGCTCTGAGGTGGGCTCCGGGGTGGTCGGGCTGGGGGCGGGCTCTGAGGTGGGCTCTGGGGTGGTCGGGCT		intron_variant	Intron 1 of 10			ENSP00000496907.1		A0A3B3IRM1

Frequencies

GnomAD3 genomes

AF:

0.0169

AC:

2436

AN:

144494

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00899

Gnomad AMI

AF:

0.00335

Gnomad AMR

AF:

0.0137

Gnomad ASJ

AF:

0.0375

Gnomad EAS

AF:

0.0630

Gnomad SAS

AF:

0.0321

Gnomad FIN

AF:

0.0237

Gnomad MID

AF:

0.0353

Gnomad NFE

AF:

0.0162

Gnomad OTH

AF:

0.0126

GnomAD2 exomes

AF:

0.0189

AC:

4641

AN:

246204

AF XY:

0.0183

show subpopulations

Gnomad AFR exome

AF:

0.00921

Gnomad AMR exome

AF:

0.0146

Gnomad ASJ exome

AF:

0.0187

Gnomad EAS exome

AF:

0.0986

Gnomad FIN exome

AF:

0.00510

Gnomad NFE exome

AF:

0.00843

Gnomad OTH exome

AF:

0.0228

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0260

AC:

37517

AN:

1443704

Hom.:

1927

AF XY:

0.0279

AC XY:

20045

AN XY:

717738

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0123

AC:

407

AN:

33048

American (AMR)

AF:

0.0194

AC:

843

AN:

43434

Ashkenazi Jewish (ASJ)

AF:

0.0610

AC:

1566

AN:

25658

East Asian (EAS)

AF:

0.216

AC:

8340

AN:

38596

South Asian (SAS)

AF:

0.0531

AC:

4489

AN:

84568

European-Finnish (FIN)

AF:

0.0572

AC:

3000

AN:

52450

Middle Eastern (MID)

AF:

0.0302

AC:

172

AN:

5694

European-Non Finnish (NFE)

AF:

0.0152

AC:

16700

AN:

1100820

Other (OTH)

AF:

0.0336

AC:

2000

AN:

59436

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.364

Heterozygous variant carriers

1968

3936

5903

7871

9839

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

260

520

780

1040

1300

<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:

0.0168

AC:

2435

AN:

144606

Hom.:

Cov.:

AF XY:

0.0164

AC XY:

1150

AN XY:

70250

show subpopulations

African (AFR)

AF:

0.00896

AC:

350

AN:

39046

American (AMR)

AF:

0.0136

AC:

199

AN:

14590

Ashkenazi Jewish (ASJ)

AF:

0.0375

AC:

124

AN:

3306

East Asian (EAS)

AF:

0.0640

AC:

295

AN:

4610

South Asian (SAS)

AF:

0.0312

AC:

138

AN:

4424

European-Finnish (FIN)

AF:

0.0237

AC:

224

AN:

9432

Middle Eastern (MID)

AF:

0.0379

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0162

AC:

1066

AN:

66000

Other (OTH)

AF:

0.0124

AC:

AN:

2012

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.407

Heterozygous variant carriers

166

248

331

414

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.00380

Hom.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Oct 26, 2016

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

May 04, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Bernard Soulier syndrome

Benign:1

May 28, 2019

Mendelics

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

0.81

Mutation Taster

=164/36

polymorphism (auto)

(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