NM_000407.5:c.47T>C

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PP4 PM2_Supporting PS4_Supporting PM3 PP3_Moderate

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:5
• Conservation: PhyloP100: -0.501
• Publications: 1 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 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GP1BB	NM_000407.5	MANE Select	c.47T>C	p.Leu16Pro	missense	Exon 2 of 2	NP_000398.1	P13224-1
	SEPT5-GP1BB	NR_037611.1		n.3787T>C		non_coding_transcript_exon	Exon 12 of 12
	SEPT5-GP1BB	NR_037612.1		n.2291T>C		non_coding_transcript_exon	Exon 12 of 12

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GP1BB	ENST00000366425.4	TSL:1 MANE Select	c.47T>C	p.Leu16Pro	missense	Exon 2 of 2	ENSP00000383382.2	P13224-1
	ENSG00000284874	ENST00000431044.5	TSL:1	n.*1132T>C		non_coding_transcript_exon	Exon 12 of 12	ENSP00000399685.1	F6X4M4
	ENSG00000284874	ENST00000455843.5	TSL:1	n.*1132T>C		non_coding_transcript_exon	Exon 12 of 12	ENSP00000391731.1	G3XAH0

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

African (AFR) AF: 0.00 AC: 0 AN: 29584

American (AMR) AF: 0.00 AC: 0 AN: 34740

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24502

East Asian (EAS) AF: 0.00 AC: 0 AN: 34282

South Asian (SAS) AF: 0.00 AC: 0 AN: 77880

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33550

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4196

European-Non Finnish (NFE) AF: 0.00000373 AC: 4 AN: 1073584

Other (OTH) AF: 0.0000525 AC: 3 AN: 57114

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	Bernard Soulier syndrome (2)
1	-	-	Macrothrombocytopenia (1)
1	-	-	not provided (1)
1	-	-	Thrombocytopenia (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		-0.50
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
PromoterAI		0.031	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1
Varity_R		0.76
gMVP		0.57
Mutation Taster		=35/65	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1601248210; hg19: chr22-19711413;