rs730882059

Variant names:

• chr22-19723410-C-G
• rs730882059
• ENST00000431044.5:n.*926C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The ENST00000431044.5(ENSG00000284874):​n.*926C>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000699 in 858,942 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000071 (0 hom.)
• Consequence: ENSG00000284874 ENST00000431044.5 non_coding_transcript_exon
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.70
• Publications: 1 publications found

Genes affected

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]

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]

GP1BB Gene-Disease associations (from GenCC):

• Bernard-Soulier syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• autosomal dominant macrothrombocytopenia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-19723410-C-G is Pathogenic according to our data. Variant chr22-19723410-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 16041.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (REVEL=0.06). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GP1BB	NM_000407.5	c.-160C>G		upstream_gene_variant		ENST00000366425.4	NP_000398.1
SEPTIN5	NM_002688.6	c.*926C>G		downstream_gene_variant		ENST00000455784.7	NP_002679.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000284874	ENST00000455843.5	n.*926C>G		non_coding_transcript_exon_variant	Exon 11 of 12	1		ENSP00000391731.1
ENSG00000284874	ENST00000455843.5	n.*926C>G		3_prime_UTR_variant	Exon 11 of 12	1		ENSP00000391731.1
GP1BB	ENST00000366425.4	c.-160C>G		upstream_gene_variant		1	NM_000407.5	ENSP00000383382.2
SEPTIN5	ENST00000455784.7	c.*926C>G		downstream_gene_variant		1	NM_002688.6	ENSP00000391311.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152252 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000761 AC: 1 AN: 131432 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000202

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000708 AC: 5 AN: 706690 Hom.: 0 Cov.: 9 AF XY: 0.00000268 AC XY: 1 AN XY: 372664

African (AFR) AF: 0.00 AC: 0 AN: 18688

American (AMR) AF: 0.00 AC: 0 AN: 34866

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20970

East Asian (EAS) AF: 0.00 AC: 0 AN: 32708

South Asian (SAS) AF: 0.00 AC: 0 AN: 65562

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33804

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4346

European-Non Finnish (NFE) AF: 0.0000109 AC: 5 AN: 460200

Other (OTH) AF: 0.00 AC: 0 AN: 35546

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152252 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74382

African (AFR) AF: 0.00 AC: 0 AN: 41472

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000340

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Bernard-Soulier syndrome, type B Pathogenic:1

Sep 06, 1996

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
BayesDel_noAF	Benign	-0.50
CADD	Benign	19
DANN	Benign	0.71
PhyloP100		1.7
PromoterAI		-0.19	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Mutation Taster		=99/201	disease causing (ClinVar)

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: rs730882059; hg19: chr22-19710933;