NM_000407.5:c.53_65delCGCCGAGCCGCCC

Variant names:

• chr22-19723891-GGCCCCGCCGAGCC-G
• NM_000407.5:c.53_65delCGCCGAGCCGCCC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000407.5(GP1BB):​c.53_65delCGCCGAGCCGCCC​(p.Pro18ArgfsTer23) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GP1BB NM_000407.5 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.72

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 28 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-19723891-GGCCCCGCCGAGCC-G is Pathogenic according to our data. Variant chr22-19723891-GGCCCCGCCGAGCC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3065872.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-19723891-GGCCCCGCCGAGCC-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GP1BB	NM_000407.5	c.53_65delCGCCGAGCCGCCC	p.Pro18ArgfsTer23	frameshift_variant	Exon 2 of 2	ENST00000366425.4	NP_000398.1
SEPT5-GP1BB	NR_037611.1	n.3793_3805delCGCCGAGCCGCCC		non_coding_transcript_exon_variant	Exon 12 of 12
SEPT5-GP1BB	NR_037612.1	n.2297_2309delCGCCGAGCCGCCC		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.53_65delCGCCGAGCCGCCC	p.Pro18ArgfsTer23	frameshift_variant	Exon 2 of 2	1	NM_000407.5	ENSP00000383382.2
ENSG00000284874	ENST00000455843.5	n.*1138_*1150delCGCCGAGCCGCCC		non_coding_transcript_exon_variant	Exon 12 of 12	1		ENSP00000391731.1
ENSG00000284874	ENST00000455843.5	n.*1138_*1150delCGCCGAGCCGCCC		3_prime_UTR_variant	Exon 12 of 12	1		ENSP00000391731.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Bernard Soulier syndrome Pathogenic:1

Mar 29, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-19711414;