rs121909750

Variant names:

• chr22-19724181-A-G
• rs121909750
• NM_000407.5:c.338A>G

Your query was ambiguous. Multiple possible variants found:

• chr22-19724181-A-G
• chr22-19724181-A-T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PS3_Supporting PP1_Moderate PP3 PP4 PM2_Supporting PS4_Moderate PM3_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000407.5(GP1BB):c.338A>G (p.Tyr113Cys) is a rare missense variant with a Grpmax Filtering allele frequency in gnomAD v4.1 is 0.00004600 (based on 4/29100 alleles in the East Asian population), which is lower than the ClinGen PD VCEP threshold (<0.00006517; PM2_Supporting). The computational predictor REVEL gives a score of 0.748, which is above the ClinGen PD VCEP threshold of >0.644 and predicts a damaging effect on function (PP3). Plasmids encoding GPIb, GPIb and GPIX were transiently transfected into 293T cells, and this variant suppressed the expression of GPIb/IX complexes (PMID:11816714; PS3_supporting). This variant has been reported in one homozygous BSS patient (PMID:11816714; PM3_supporting) and one compound heterozygous BSS patient (PMID:24051937) with in trans variant Arg82Cys (classified VUS by the PD VCEP). At least one patient (PMID:11816714) with this variant had aggregation absent for ristocetin and present for all other agonists and GPIb was detectable in reduced amounts on platelet surfaces by flow cytometry, which is highly specific for Bernard-Soulier syndrome (PP4). Additionally, the patient had excessive mucocutaneous bleeding and macrothrombocytopenia which are consistent with Bernard-Soulier syndrome. Seven individuals heterozygous for the variant are considered informative due to measurable, quantitative abnormalities relevant to the disease (i.e. significantly reduced platelet surface expression of GP1b, giant platelets, and macrothrombocytopenia) in PMIDs: 11816714 and 28064200 (PS4_moderate). Plus there was segregation of this variant in 5 additional informative heterozygous family members (PMID:28064200 and PMID:11816714; PP1). In summary this variant is classified as Likely Pathogenic using the ACMG criteria specified by the PD VCEP: PS4_Moderate, PS3_supporting, PM2_supporting, PM3_supporting, PP1, PP3, and PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA126154/MONDO:0009276/082

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000045 (0 hom.)
• Consequence: GP1BB NM_000407.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 0.365
• Publications: 5 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: Likely_pathogenic. The variant received 9 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GP1BB	NM_000407.5	c.338A>G	p.Tyr113Cys	missense_variant	Exon 2 of 2	ENST00000366425.4	NP_000398.1
SEPT5-GP1BB	NR_037611.1	n.4078A>G		non_coding_transcript_exon_variant	Exon 12 of 12
SEPT5-GP1BB	NR_037612.1	n.2582A>G		non_coding_transcript_exon_variant	Exon 12 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GP1BB	ENST00000366425.4	c.338A>G	p.Tyr113Cys	missense_variant	Exon 2 of 2	1	NM_000407.5	ENSP00000383382.2
ENSG00000284874	ENST00000455843.5	n.*1423A>G		non_coding_transcript_exon_variant	Exon 12 of 12	1		ENSP00000391731.1
ENSG00000284874	ENST00000455843.5	n.*1423A>G		3_prime_UTR_variant	Exon 12 of 12	1		ENSP00000391731.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000451 AC: 5 AN: 1108830 Hom.: 0 Cov.: 31 AF XY: 0.00000562 AC XY: 3 AN XY: 534278

African (AFR) AF: 0.00 AC: 0 AN: 22130

American (AMR) AF: 0.00 AC: 0 AN: 8776

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14226

East Asian (EAS) AF: 0.000167 AC: 4 AN: 23936

South Asian (SAS) AF: 0.00 AC: 0 AN: 30704

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22748

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2940

European-Non Finnish (NFE) AF: 0.00000106 AC: 1 AN: 939484

Other (OTH) AF: 0.00 AC: 0 AN: 43886

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

MACROTHROMBOCYTOPENIA, FAMILIAL, BERNARD-SOULIER TYPE Pathogenic:1

Apr 01, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Bernard Soulier syndrome Pathogenic:1

Feb 11, 2025

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000407.5(GP1BB):c.338A>G (p.Tyr113Cys) is a rare missense variant with a Grpmax Filtering allele frequency in gnomAD v4.1 is 0.00004600 (based on 4/29100 alleles in the East Asian population), which is lower than the ClinGen PD VCEP threshold (<0.00006517; PM2_Supporting). The computational predictor REVEL gives a score of 0.748, which is above the ClinGen PD VCEP threshold of >0.644 and predicts a damaging effect on function (PP3). Plasmids encoding GPIb, GPIb and GPIX were transiently transfected into 293T cells, and this variant suppressed the expression of GPIb/IX complexes (PMID: 11816714; PS3_supporting). This variant has been reported in one homozygous BSS patient (PMID: 11816714; PM3_supporting) and one compound heterozygous BSS patient (PMID: 24051937) with in trans variant Arg82Cys (classified VUS by the PD VCEP). At least one patient (PMID: 11816714) with this variant had aggregation absent for ristocetin and present for all other agonists and GPIb was detectable in reduced amounts on platelet surfaces by flow cytometry, which is highly specific for Bernard-Soulier syndrome (PP4). Additionally, the patient had excessive mucocutaneous bleeding and macrothrombocytopenia which are consistent with Bernard-Soulier syndrome. Seven individuals heterozygous for the variant are considered informative due to measurable, quantitative abnormalities relevant to the disease (i.e. significantly reduced platelet surface expression of GP1b, giant platelets, and macrothrombocytopenia) in PMIDs: 11816714 and 28064200 (PS4_moderate). Plus there was segregation of this variant in 5 additional informative heterozygous family members (PMID: 28064200 and PMID: 11816714; PP1). In summary this variant is classified as Likely Pathogenic using the ACMG criteria specified by the PD VCEP: PS4_Moderate, PS3_supporting, PM2_supporting, PM3_supporting, PP1, PP3, and PP4. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Benign	0.15
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.54	T
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		0.36
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.045	D
Polyphen		0.98	D
Vest4		0.84
MutPred		0.76		Loss of phosphorylation at Y113 (P = 0.0531);
MVP		0.99
MPC		1.9
ClinPred		0.97	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.59
gMVP		0.59
Mutation Taster		=31/69	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: rs121909750; hg19: chr22-19711704;