rs121918447

Positions:

• chr17-47310169-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PS3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000212.2(ITGB3):c.2332T>C (p.Ser778Pro) missense variant has been reported in at one Glanzmann thrombasthenia patient (PMID:1438206). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The receptor function of αIIbβ3, measured by functional flow cytometry, in CHO cells transiently co-transfected with the Ser778Pro variant β3 and wild type αIIb showed minimal binding to ligand mimetic antibody PAC-1 indicating that this variant impacts protein function (PMID:8080992; PS3). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PS3, PM2_supporitng. (VCEP specifications version 2; date of approval 11/04/2021). LINK:https://erepo.genome.network/evrepo/ui/classification/CA123230/MONDO:0100326/011

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITGB3 ENST00000559488.7 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1
• Conservation: PhyloP100: 5.56

Genes affected

ITGB3 (HGNC:6156): (integrin subunit beta 3) The ITGB3 protein product is the integrin beta chain beta 3. Integrins are integral cell-surface proteins composed of an alpha chain and a beta chain. A given chain may combine with multiple partners resulting in different integrins. Integrin beta 3 is found along with the alpha IIb chain in platelets. Integrins are known to participate in cell adhesion as well as cell-surface mediated signalling. [provided by RefSeq, Jul 2008]

EFCAB13-DT (HGNC:55338): (EFCAB13 divergent transcript)

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PS3: 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
ITGB3	NM_000212.3	c.2332T>C	p.Ser778Pro	missense_variant	15/15	ENST00000559488.7	NP_000203.2
EFCAB13-DT	NR_110880.1	n.363-6387A>G		intron_variant, non_coding_transcript_variant
EFCAB13-DT	NR_110881.1	n.227-6387A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITGB3	ENST00000559488.7	c.2332T>C	p.Ser778Pro	missense_variant	15/15	1	NM_000212.3	ENSP00000452786	P1
EFCAB13-DT	ENST00000575039.1	n.227-6387A>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Glanzmann thrombasthenia 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 1992

- -

Glanzmann thrombasthenia Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

Nov 04, 2021

The NM_000212.2(ITGB3):c.2332T>C (p.Ser778Pro) missense variant has been reported in at one Glanzmann thrombasthenia patient (PMID: 1438206). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The receptor function of αIIbβ3, measured by functional flow cytometry, in CHO cells transiently co-transfected with the Ser778Pro variant β3 and wild type αIIb showed minimal binding to ligand mimetic antibody PAC-1 indicating that this variant impacts protein function (PMID: 8080992; PS3). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PS3, PM2_supporitng. (VCEP specifications version 2; date of approval 11/04/2021). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.0014	D
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.0	D
Sift	Benign	0.031	D
Sift4G	Uncertain	0.032	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.89		Loss of MoRF binding (P = 0.0739);
MVP		0.97
MPC		1.4
ClinPred		0.95	D
GERP RS		6.0
Varity_R		0.95
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs121918447; hg19: chr17-45387535;