22-19723962-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM1 BP4_Strong BP6_Very_Strong BS2

The NM_000407.5(GP1BB):c.119G>A(p.Gly40Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00157 in 1,524,650 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (6 hom.)
• Consequence: GP1BB NM_000407.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.521

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]

SEPT5-GP1BB (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 Benign. Variant got -14 ACMG points.

• PM1: In a chain Platelet glycoprotein Ib beta chain (size 180) in uniprot entity GP1BB_HUMAN there are 37 pathogenic changes around while only 2 benign (95%) in NM_000407.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.054804713).
• BP6: Variant 22-19723962-G-A is Benign according to our data. Variant chr22-19723962-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 731652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GP1BB	NM_000407.5	c.119G>A	p.Gly40Glu	missense_variant	2/2	ENST00000366425.4
SEPT5-GP1BB	NR_037611.1	n.3859G>A		non_coding_transcript_exon_variant	12/12
SEPT5-GP1BB	NR_037612.1	n.2363G>A		non_coding_transcript_exon_variant	12/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GP1BB	ENST00000366425.4	c.119G>A	p.Gly40Glu	missense_variant	2/2	1	NM_000407.5	P1
SEPTIN5	ENST00000470814.1	n.2091G>A		non_coding_transcript_exon_variant	6/6	5

Frequencies

GnomAD3 genomes AF: 0.00116 AC: 176 AN: 152128 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.00129

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00153 AC: 185 AN: 120936 Hom.: 2 AF XY: 0.00145 AC XY: 98 AN XY: 67358

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.00232

Gnomad ASJ exome AF: 0.00118

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000999

Gnomad FIN exome AF: 0.000786

Gnomad NFE exome AF: 0.00174

Gnomad OTH exome AF: 0.00304

GnomAD4 exome AF: 0.00161 AC: 2211 AN: 1372414 Hom.: 6 Cov.: 32 AF XY: 0.00163 AC XY: 1108 AN XY: 678074

Gnomad4 AFR exome AF: 0.000380

Gnomad4 AMR exome AF: 0.00233

Gnomad4 ASJ exome AF: 0.00138

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00101

Gnomad4 FIN exome AF: 0.000922

Gnomad4 NFE exome AF: 0.00174

Gnomad4 OTH exome AF: 0.00178

GnomAD4 genome AF: 0.00116 AC: 176 AN: 152236 Hom.: 0 Cov.: 33 AF XY: 0.00105 AC XY: 78 AN XY: 74426

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.00333

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.000472

Gnomad4 NFE AF: 0.00129

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00156 Hom.: 1

Bravo AF: 0.00139

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000564 AC: 4

ExAC AF: 0.000715 AC: 73

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	GP1BB: PP3, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

Bernard Soulier syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 11, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.070
Cadd	Uncertain	23
Dann	Benign	0.97
DEOGEN2	Benign	0.26	T
Eigen	Benign	0.14
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.99	D
MetaRNN	Benign	0.055	T
MetaSVM	Uncertain	0.22	D
MutationAssessor	Benign	0.46	N
MutationTaster	Benign	0.89	N
PROVEAN	Benign	0.17	N
REVEL	Uncertain	0.56
Sift	Benign	0.10	T
Sift4G	Uncertain	0.014	D
Polyphen		1.0	D
Vest4		0.50
MVP		1.0
MPC		2.0
ClinPred		0.026	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.54

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

Publications

LitVar

Other links and lift over

dbSNP: rs375285857; hg19: chr22-19711485; COSMIC: COSV100820479; COSMIC: COSV100820479;