NM_000407.5:c.80C>T

Variant names:

• chr22-19723923-C-T
• rs2145795850
• NM_000407.5:c.80C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Moderate PP5_Moderate

The NM_000407.5(GP1BB):​c.80C>T​(p.Pro27Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000219 in 1,370,794 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: 0.0000022 (0 hom.)
• Consequence: GP1BB NM_000407.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.08
• Publications: 0 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.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 14 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 0.45873 (below the threshold of 3.09). Trascript score misZ: -2.9917 (below the threshold of 3.09). GenCC associations: The gene is linked to Bernard-Soulier syndrome, autosomal dominant macrothrombocytopenia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.849
• PP5: Variant 22-19723923-C-T is Pathogenic according to our data. Variant chr22-19723923-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1691234.Status of the report is criteria_provided_single_submitter, 1 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GP1BB	NM_000407.5	MANE Select	c.80C>T	p.Pro27Leu	missense	Exon 2 of 2	NP_000398.1	P13224-1
	SEPT5-GP1BB	NR_037611.1		n.3820C>T		non_coding_transcript_exon	Exon 12 of 12
	SEPT5-GP1BB	NR_037612.1		n.2324C>T		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.80C>T	p.Pro27Leu	missense	Exon 2 of 2	ENSP00000383382.2	P13224-1
	ENSG00000284874	ENST00000431044.5	TSL:1	n.*1165C>T		non_coding_transcript_exon	Exon 12 of 12	ENSP00000399685.1	F6X4M4
	ENSG00000284874	ENST00000455843.5	TSL:1	n.*1165C>T		non_coding_transcript_exon	Exon 12 of 12	ENSP00000391731.1	G3XAH0

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000219 AC: 3 AN: 1370794 Hom.: 0 Cov.: 32 AF XY: 0.00000148 AC XY: 1 AN XY: 676408

African (AFR) AF: 0.0000340 AC: 1 AN: 29418

American (AMR) AF: 0.00 AC: 0 AN: 34852

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24630

East Asian (EAS) AF: 0.00 AC: 0 AN: 34212

South Asian (SAS) AF: 0.00 AC: 0 AN: 78168

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33908

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4406

European-Non Finnish (NFE) AF: 0.00000186 AC: 2 AN: 1074080

Other (OTH) AF: 0.00 AC: 0 AN: 57120

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Bernard Soulier syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		4.1
PROVEAN	Pathogenic	-8.2	D
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.43
MutPred		0.54		Gain of stability (P = 0.0106)
MVP		0.97
MPC		0.70
ClinPred		1.0	D
GERP RS		3.8
PromoterAI		0.0058	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.1
Varity_R		0.91
gMVP		0.69
Mutation Taster		=60/40	polymorphism

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: rs2145795850; hg19: chr22-19711446;