22-19723570-A-T

Position:

• chr22-19723570-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000407.5:c.1A>T (p.Met1Leu) variant in GP1BB may cause a truncated or absent protein by altering the start codon of the coding sequence and is predicted to lead to the omission of a critical region of the protein. There is no alternative in-frame methionine in GP1BB (PVS1). The Grpmax filtering allele frequency in gnomaDv4.1is 6.800e-7 (based on 3/1176548 alleles) in the European (non-Finnish) population, which is below the <0.0000651678 threshold for PM2_supporting. One heterozygous macrothrombocytopenia patient has been reported with this variant (PMID:28983057; PS4_NotMet). 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: PVS1 and PM2_Supporting (VCEP specifications 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA410676172/MONDO:0009276/082

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GP1BB NM_000407.5 initiator_codon
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.75

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 9 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GP1BB	NM_000407.5	c.1A>T	p.Met1?	initiator_codon_variant	1/2	ENST00000366425.4	NP_000398.1
SEPT5-GP1BB	NR_037611.1	n.3741A>T		non_coding_transcript_exon_variant	11/12
SEPT5-GP1BB	NR_037612.1	n.2245A>T		non_coding_transcript_exon_variant	11/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GP1BB	ENST00000366425.4	c.1A>T	p.Met1?	initiator_codon_variant	1/2	1	NM_000407.5	ENSP00000383382.2
ENSG00000284874	ENST00000455843.5	n.*1086A>T		non_coding_transcript_exon_variant	11/12	1		ENSP00000391731.1
ENSG00000284874	ENST00000455843.5	n.*1086A>T		3_prime_UTR_variant	11/12	1		ENSP00000391731.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000208 AC: 3 AN: 1444864 Hom.: 0 Cov.: 31 AF XY: 0.00000418 AC XY: 3 AN XY: 718488

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000271

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Mild macrothrombocytopenia Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

-

- -

Bernard Soulier syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	24
DANN	Benign	0.81
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.52
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Benign	-0.70	T
PROVEAN	Benign	-0.69	N
REVEL	Uncertain	0.44
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.064	B
Vest4		0.85
MutPred		0.98		Loss of catalytic residue at M1 (P = 0.1307);
MVP		0.86
ClinPred		0.83	D
GERP RS		2.2
Varity_R		0.78
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1389191920; hg19: chr22-19711093;