rs121909752

Variant names:

• chr22-19723980-G-A
• rs121909752
• NM_000407.5:c.137G>A

Your query was ambiguous. Multiple possible variants found:

• chr22-19723980-G-A
• chr22-19723980-G-C
• chr22-19723980-G-T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000407.5(GP1BB):​c.137G>A​(p.Trp46*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000021 in 1,380,272 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: GP1BB NM_000407.5 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: -0.520
• Publications: 3 publications found

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]

ENSG00000284874 (HGNC:):

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]

ACMG classification

Our verdict: Pathogenic. The variant received 16 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 31 pathogenic variants in the truncated region.
• PP5: Variant 22-19723980-G-A is Pathogenic according to our data. Variant chr22-19723980-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 16040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GP1BB	NM_000407.5	MANE Select	c.137G>A	p.Trp46*	stop_gained	Exon 2 of 2	NP_000398.1
	SEPT5-GP1BB	NR_037611.1		n.3877G>A		non_coding_transcript_exon	Exon 12 of 12
	SEPT5-GP1BB	NR_037612.1		n.2381G>A		non_coding_transcript_exon	Exon 12 of 12

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GP1BB	ENST00000366425.4	TSL:1 MANE Select	c.137G>A	p.Trp46*	stop_gained	Exon 2 of 2	ENSP00000383382.2
	ENSG00000284874	ENST00000431044.5	TSL:1	n.*1222G>A		non_coding_transcript_exon	Exon 12 of 12	ENSP00000399685.1
	ENSG00000284874	ENST00000455843.5	TSL:1	n.*1222G>A		non_coding_transcript_exon	Exon 12 of 12	ENSP00000391731.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000210 AC: 29 AN: 1380272 Hom.: 0 Cov.: 32 AF XY: 0.0000264 AC XY: 18 AN XY: 682602

African (AFR) AF: 0.00 AC: 0 AN: 29306

American (AMR) AF: 0.00 AC: 0 AN: 36412

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24726

East Asian (EAS) AF: 0.00 AC: 0 AN: 34488

South Asian (SAS) AF: 0.00 AC: 0 AN: 78438

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35338

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5170

European-Non Finnish (NFE) AF: 0.0000269 AC: 29 AN: 1078934

Other (OTH) AF: 0.00 AC: 0 AN: 57460

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bernard-Soulier syndrome, type B Pathogenic:1

Jul 15, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Macrothrombocytopenia Pathogenic:1

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Increased mean platelet volume Pathogenic:1

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Bernard Soulier syndrome Pathogenic:1

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Thrombocytopenia Pathogenic:1

Feb 01, 2019

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	35
DANN	Benign	0.94
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.49	N
PhyloP100		-0.52
Vest4		0.075
GERP RS		-4.7
PromoterAI		0.080	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Mutation Taster		=20/180	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121909752; hg19: chr22-19711503;