chr22-19724240-G-C

Variant names:

• chr22-19724240-G-C
• rs121909751
• NM_000407.5:c.397G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PS3_Supporting PP4 PP1 PM2_Supporting PM3

This summary comes from the ClinGen Evidence Repository: The missense variant NM_000407.5(GP1BB):c.397G>C (p.Ala133Pro) has a Grpmax Filtering allele frequency in gnomAD v4.1 is 0.00002722 (based on 3/29196 alleles) in the East Asian population, which is lower than the ClinGen PD VCEP threshold (<0.00006517; PM2_Supporting). At least one patient (Patient A.K. in PMID:9116284) with this variant had aggregation absent for ristocetin and present for all other agonists and flow cytometry found the expression of GPIbα, the GPIb/IX complex, and GPIX were remarkably lower than the normal control. 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. The patient is compound heterozygote has been reported with Tyr113Cys (provisionally classified Likely Pathogenic by PD VCEP) and Ala133Pro confirmed in trans from heterozygous parents (PMID:9116284; PM3). There is segregation of this variant in 1 additional compound heterozygous BSS family member (PMID:9116284; total 1pt, PP1). In transiently transfected CHO cells HA-GPIbβ was present on the cell surface but GPIX was not (PMID:21908432). In transiently transfected CHO cells HA-GPIbβ was present on the cell surface around 20% but GPIX was absent (PMID:21908432; PS3_supporting). 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: PS3_supporting, PM3, PM2_supporting, PP1, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA126156/MONDO:0009276/082

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000037 (0 hom.)
• Consequence: GP1BB NM_000407.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -0.0460

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 6 ACMG points.

• PS3: 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.
• 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.397G>C	p.Ala133Pro	missense_variant	Exon 2 of 2	ENST00000366425.4	NP_000398.1
SEPT5-GP1BB	NR_037611.1	n.4137G>C		non_coding_transcript_exon_variant	Exon 12 of 12
SEPT5-GP1BB	NR_037612.1	n.2641G>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.397G>C	p.Ala133Pro	missense_variant	Exon 2 of 2	1	NM_000407.5	ENSP00000383382.2
ENSG00000284874	ENST00000455843.5	n.*1482G>C		downstream_gene_variant		1		ENSP00000391731.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000367 AC: 4 AN: 1088936 Hom.: 0 Cov.: 31 AF XY: 0.00000770 AC XY: 4 AN XY: 519240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000125

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000108

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.35	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.42	T
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.20	N
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.50
Sift	Benign	0.23	T
Sift4G	Benign	0.21	T
Polyphen		0.027	B
Vest4		0.69
MutPred		0.78		Gain of disorder (P = 0.0562);
MVP		0.92
MPC		0.93
ClinPred		0.12	T
GERP RS		0.50
Varity_R		0.71
gMVP		0.67

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

Other links and lift over

dbSNP: rs121909751; hg19: chr22-19711763;