chr22-19723970-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM3_SupportingPP3_Moderate

This summary comes from the ClinGen Evidence Repository: The c.127G>T variant in GP1BB is a missense variant predicted to cause substitution of Glycine by Tryptophan at amino acid 43 (p.Gly43Trp). The computational predictor REVEL gives a score of 0.887, which is above the ClinGen PD VCEP threshold of >0.773 and predicts a damaging effect on function (PP3_Moderate). Patient BSS64 (PMID:24934643) is reported homozygous (PM3_supporting). In summary, this variant meets the criteria to be classified as Uncertain significance - insufficient evidence for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP3_Moderate, PM2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10102316/MONDO:0009276/082

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

GP1BB
NM_000407.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:1U:2

Conservation

PhyloP100: 0.888

Publications

1 publications found

Variant links:

Genes affected

GP1BB (HGNC:4440): (glycoprotein Ib platelet subunit beta) Platelet glycoprotein Ib (GPIb) is a heterodimeric transmembrane protein consisting of a disulfide-linked 140 kD alpha chain and 22 kD beta chain. It is part of the GPIb-V-IX system that constitutes the receptor for von Willebrand factor (VWF), and mediates platelet adhesion in the arterial circulation. GPIb alpha chain provides the VWF binding site, and GPIb beta contributes to surface expression of the receptor and participates in transmembrane signaling through phosphorylation of its intracellular domain. Mutations in the GPIb beta subunit have been associated with Bernard-Soulier syndrome, velocardiofacial syndrome and giant platelet disorder. The 206 amino acid precursor of GPIb beta is synthesized from a 1.0 kb mRNA expressed in plateletes and megakaryocytes. A 411 amino acid protein arising from a longer, unspliced transcript in endothelial cells has been described; however, the authenticity of this product has been questioned. Yet another less abundant GPIb beta mRNA species of 3.5 kb, expressed in nonhematopoietic tissues such as endothelium, brain and heart, was shown to result from inefficient usage of a non-consensus polyA signal in the neighboring upstream gene (SEPT5, septin 5). In the absence of polyadenylation from its own imperfect site, the SEPT5 gene produces read-through transcripts that use the consensus polyA signal of this gene. [provided by RefSeq, Dec 2010]

GP1BB links:

ENSG00000284874 (HGNC:):

ENSG00000284874 links:

SEPTIN5 (HGNC:9164): (septin 5) This gene is a member of the septin gene family of nucleotide binding proteins, originally described in yeast as cell division cycle regulatory proteins. Septins are highly conserved in yeast, Drosophila, and mouse and appear to regulate cytoskeletal organization. Disruption of septin function disturbs cytokinesis and results in large multinucleate or polyploid cells. This gene is mapped to 22q11, the region frequently deleted in DiGeorge and velocardiofacial syndromes. A translocation involving the MLL gene and this gene has also been reported in patients with acute myeloid leukemia. Alternative splicing results in multiple transcript variants. The presence of a non-consensus polyA signal (AACAAT) in this gene also results in read-through transcription into the downstream neighboring gene (GP1BB; platelet glycoprotein Ib), whereby larger, non-coding transcripts are produced. [provided by RefSeq, Dec 2010]

SEPTIN5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM3

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000407.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GP1BB	NM_000407.5	MANE Select	c.127G>T	p.Gly43Trp	missense	Exon 2 of 2	NP_000398.1	P13224-1
SEPT5-GP1BB	NR_037611.1		n.3867G>T		non_coding_transcript_exon	Exon 12 of 12
SEPT5-GP1BB	NR_037612.1		n.2371G>T		non_coding_transcript_exon	Exon 12 of 12

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GP1BB	ENST00000366425.4	TSL:1 MANE Select	c.127G>T	p.Gly43Trp	missense	Exon 2 of 2	ENSP00000383382.2	P13224-1
ENSG00000284874	ENST00000431044.5	TSL:1	n.*1212G>T		non_coding_transcript_exon	Exon 12 of 12	ENSP00000399685.1	F6X4M4
ENSG00000284874	ENST00000455843.5	TSL:1	n.*1212G>T		non_coding_transcript_exon	Exon 12 of 12	ENSP00000391731.1	G3XAH0

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000479

AC:

AN:

125376

AF XY:

0.0000715

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000828

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000610

Gnomad OTH exome

AF:

0.000270

GnomAD4 exome

AF:

0.0000291

AC:

AN:

1374848

Hom.:

Cov.:

AF XY:

0.0000383

AC XY:

AN XY:

679538

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29018

American (AMR)

AF:

0.0000843

AC:

AN:

35606

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24630

East Asian (EAS)

AF:

0.00

AC:

AN:

34056

South Asian (SAS)

AF:

0.00

AC:

AN:

78036

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34944

Middle Eastern (MID)

AF:

0.000197

AC:

AN:

5076

European-Non Finnish (NFE)

AF:

0.0000297

AC:

AN:

1076238

Other (OTH)

AF:

0.0000699

AC:

AN:

57244

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

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:

0.0000394

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41562

American (AMR)

AF:

0.0000654

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

67980

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.533

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:

0.000142

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000285

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Macrothrombocytopenia (2)

Bernard Soulier syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.79

Eigen

Uncertain

0.23

Eigen_PC

Benign

0.010

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.62

M_CAP

Pathogenic

0.99

MetaRNN

Pathogenic

0.96

MetaSVM

Uncertain

0.66

MutationAssessor

Pathogenic

2.9

PhyloP100

0.89

PROVEAN

Pathogenic

-5.9

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.71

MutPred

0.84

Loss of disorder (P = 0.0479)

MVP

0.97

MPC

1.9

ClinPred

0.65

GERP RS

1.6

PromoterAI

0.025

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.56

gMVP

0.52

Mutation Taster

=25/75

disease causing (ClinVar)

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over