chr17-47253863-T-C

Position:

chr17-47253863-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2_SupportingPM3_SupportingPVS1_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000212.3(ITGB3):c.2T>C (p.Met1Thr) 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. At least one variant (c.31T>C; p.Trp11Arg) has been classified Pathogenic upstream of the next potential in-frame start codon at residue 48 (PVS1_Moderate). Patient 1, of PMID:31029159, is reported to have a clinical diagnosis of GT and is homozygous for this variant (PM3_supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). 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: PVS1_moderate, PM2_supporting, PM3_supporting (VCEP specifications version 2.1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA400028186/MONDO:0100326/011

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

ITGB3
NM_000212.3 start_lost

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:1

Conservation

PhyloP100: 0.577

Variant links:

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]

ITGB3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 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.

PM3

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 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	1/15	ENST00000559488.7	NP_000203.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITGB3	ENST00000559488.7 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	1/15	1	NM_000212.3	ENSP00000452786	P1	P05106-1
ITGB3	ENST00000571680.1 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	1/9	1		ENSP00000461626
ITGB3	ENST00000696963.1 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	1/14			ENSP00000513002		P05106-2

Frequencies

GnomAD3 genomes

AF:

0.00000662

AC:

AN:

151136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000244

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000120

AC:

AN:

1083546

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

516328

show subpopulations

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:

0.0000141

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000662

AC:

AN:

151136

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73812

show subpopulations

Gnomad4 AFR

AF:

0.0000244

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glanzmann thrombasthenia

Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

Apr 06, 2023

The NM_000212.3(ITGB3):c.2T>C (p.Met1Thr) 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. At least one variant (c.31T>C; p.Trp11Arg) has been classified Pathogenic upstream of the next potential in-frame start codon at residue 48 (PVS1_Moderate). Patient 1, of PMID: 31029159, is reported to have a clinical diagnosis of GT and is homozygous for this variant (PM3_supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). 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: PVS1_moderate, PM2_supporting, PM3_supporting (VCEP specifications version 2.1). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Uncertain

0.030

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.32

T;.

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.28

FATHMM_MKL

Benign

0.14

LIST_S2

Uncertain

0.90

D;D

M_CAP

Pathogenic

0.89

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Benign

-0.92

MutationTaster

Benign

1.0

D;D;D

PROVEAN

Benign

-0.52

N;.

Sift

Pathogenic

0.0

D;.

Sift4G

Benign

0.11

T;T

Polyphen

0.0

B;.

Vest4

0.62

MutPred

0.99

Gain of phosphorylation at M1 (P = 0.0057);Gain of phosphorylation at M1 (P = 0.0057);

MVP

0.99

ClinPred

1.0

GERP RS

2.1

Varity_R

0.89

gMVP

0.85

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over