22-19723890-T-C

Variant names:

• chr22-19723890-T-C
• rs1601248210
• NM_000407.5:c.47T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2_Supporting PS4_Supporting PP3_Moderate PM3 PP4

This summary comes from the ClinGen Evidence Repository: NM_000407.5(GP1BB):c.47T>C (p.Leu16Pro) is a missense variant in GP1BB that has been reported in the literature in at least two probands diagnosed with Bernard-Soulier syndrome in the homozygous state (PM3, PMIDs:32419170, 24934643). One of those patients displayed absent expression of GP1bb (CD42) in addition to excessive mucocutaneous bleeding and macrothrombocytopenia (PP4). At least 5 unrelated individuals heterozygous for this variant have been reported with macrothrombocytopenia (<150x10^9 platelets/l and MPV >12) in four publications (PMIDs: 28064200, 36173017, 31793234, 30609015; PS4_supporting). The Grpmax filtering allele frequency in gnomaDv4.1 is 8.200e-7 (based on 4/1141542 alleles) in the European (non-Finnish) population, which is below the <0.0000651678 threshold for PM2_supporting. Additionally, the variant is predicted to have a deleterious effect (REVEL score of 0.886; PP3_Moderate). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive Bernard-Soulier syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PS4_Supporting, PM2_Supporting, PP3_Moderate, PP4, and PM3 (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA410676273/MONDO:0009276/082

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000051 (0 hom.)
• Consequence: GP1BB NM_000407.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: -0.501

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

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• 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.
• 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.47T>C	p.Leu16Pro	missense_variant	Exon 2 of 2	ENST00000366425.4	NP_000398.1
SEPT5-GP1BB	NR_037611.1	n.3787T>C		non_coding_transcript_exon_variant	Exon 12 of 12
SEPT5-GP1BB	NR_037612.1	n.2291T>C		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.47T>C	p.Leu16Pro	missense_variant	Exon 2 of 2	1	NM_000407.5	ENSP00000383382.2
ENSG00000284874	ENST00000455843.5	n.*1132T>C		non_coding_transcript_exon_variant	Exon 12 of 12	1		ENSP00000391731.1
ENSG00000284874	ENST00000455843.5	n.*1132T>C		3_prime_UTR_variant	Exon 12 of 12	1		ENSP00000391731.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000511 AC: 7 AN: 1369432 Hom.: 0 Cov.: 32 AF XY: 0.00000592 AC XY: 4 AN XY: 675538

Gnomad4 AFR exome AF: 0.00

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: 0.00000373

Gnomad4 OTH exome AF: 0.0000525

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:1

Feb 16, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24934643, 30609015, 28064200, 32581362, 31793234, 32419170, 31064749) -

Macrothrombocytopenia 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: 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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.42	T
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Uncertain	2.6	M
PROVEAN	Benign	-2.2	N
REVEL	Pathogenic	0.89
Sift	Benign	0.030	D
Sift4G	Benign	0.067	T
Polyphen		0.91	P
Vest4		0.89
MutPred		0.42		Gain of loop (P = 0.0013);
MVP		0.96
MPC		1.1
ClinPred		0.51	D
GERP RS		2.8
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1
Varity_R		0.76
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs1601248210; hg19: chr22-19711413;