22-19723980-G-C

Position:

chr22-19723980-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_000407.5(GP1BB):c.137G>C(p.Trp46Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000783 in 1,532,362 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000080 ( 0 hom. )

Consequence

GP1BB
NM_000407.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.520

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a chain Platelet glycoprotein Ib beta chain (size 180) in uniprot entity GP1BB_HUMAN there are 22 pathogenic changes around while only 0 benign (100%) in NM_000407.5

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21707323).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GP1BB	NM_000407.5 linkuse as main transcript	c.137G>C	p.Trp46Ser	missense_variant	2/2	ENST00000366425.4	NP_000398.1	P13224-1
SEPT5-GP1BB	NR_037611.1 linkuse as main transcript	n.3877G>C		non_coding_transcript_exon_variant	12/12
SEPT5-GP1BB	NR_037612.1 linkuse as main transcript	n.2381G>C		non_coding_transcript_exon_variant	12/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
GP1BB	ENST00000366425.4 linkuse as main transcript	c.137G>C	p.Trp46Ser	missense_variant	2/2	1	NM_000407.5	ENSP00000383382.2	P13224-1
ENSG00000284874	ENST00000455843.5 linkuse as main transcript	n.*1222G>C		non_coding_transcript_exon_variant	12/12	1		ENSP00000391731.1	G3XAH0
ENSG00000284874	ENST00000455843.5 linkuse as main transcript	n.*1222G>C		3_prime_UTR_variant	12/12	1		ENSP00000391731.1	G3XAH0

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000753

AC:

AN:

132770

Hom.:

AF XY:

0.0000135

AC XY:

AN XY:

74072

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000187

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000797

AC:

AN:

1380272

Hom.:

Cov.:

AF XY:

0.00000879

AC XY:

AN XY:

682602

show subpopulations

Gnomad4 AFR exome

AF:

0.000171

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000185

Gnomad4 OTH exome

AF:

0.0000174

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152090

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.74

DEOGEN2

Benign

0.33

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.36

M_CAP

Pathogenic

0.83

MetaRNN

Benign

0.22

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.69

PROVEAN

Benign

-1.0

REVEL

Benign

0.19

Sift

Benign

0.69

Sift4G

Benign

0.76

Polyphen

0.0050

Vest4

0.14

MutPred

0.53

Gain of disorder (P = 6e-04);

MVP

0.61

MPC

1.1

ClinPred

0.016

GERP RS

-4.7

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.7

Varity_R

0.42

gMVP

0.35

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over