17-47283385-T-G

Position:

chr17-47283385-T-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The NM_000212.3(ITGB3):c.197T>G (p.Leu66Arg) missense variant was observed by Illumina as part of a predisposition screen in an ostensibly healthy population and has been reported in the literature in a blood donor cohort (PMID:32110192) but has not been reported in a GT patient. There is not consensus among computational evidence as to whether there is an effect on the gene or gene product. The variant occurs at a frequency in gnomAD v4.0.0 of 0.002756 (3252/1180038 alleles) in the European (non-Finnish) population, which is higher than the ClinGen PD VCEP BA1 threshold (>0.0024), and therefore meets this criterion (BA1). In summary this variant meets criteria for classification as Benign for Glanzmann thrombasthenia. GT-specific criteria applied: BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8622895/MONDO:0010119/011

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0024 ( 9 hom. )

Consequence

ITGB3
NM_000212.3 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:2B:4

Conservation

PhyloP100: 6.25

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BA1

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.197T>G	p.Leu66Arg	missense_variant	3/15	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.197T>G	p.Leu66Arg	missense_variant	3/15	1	NM_000212.3	ENSP00000452786	P1	P05106-1
ITGB3	ENST00000571680.1 linkuse as main transcript	c.197T>G	p.Leu66Arg	missense_variant	3/9	1		ENSP00000461626
ITGB3	ENST00000696963.1 linkuse as main transcript	c.197T>G	p.Leu66Arg	missense_variant	3/14			ENSP00000513002		P05106-2

Frequencies

GnomAD3 genomes

AF:

0.00152

AC:

232

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00216

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00251

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.00177

AC:

444

AN:

251368

Hom.:

AF XY:

0.00183

AC XY:

248

AN XY:

135856

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.00107

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00199

Gnomad FIN exome

AF:

0.00388

Gnomad NFE exome

AF:

0.00215

Gnomad OTH exome

AF:

0.00179

GnomAD4 exome

AF:

0.00245

AC:

3580

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00234

AC XY:

1705

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.00127

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00169

Gnomad4 FIN exome

AF:

0.00374

Gnomad4 NFE exome

AF:

0.00277

Gnomad4 OTH exome

AF:

0.00137

GnomAD4 genome

AF:

0.00152

AC:

232

AN:

152350

Hom.:

Cov.:

AF XY:

0.00149

AC XY:

111

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.000385

Gnomad4 AMR

AF:

0.000719

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00216

Gnomad4 NFE

AF:

0.00251

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.00218

Hom.:

Bravo

AF:

0.00139

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00244

AC:

ExAC

AF:

0.00167

AC:

203

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00174

EpiControl

AF:

0.00148

ClinVar

Significance: Benign

Submissions summary: Uncertain:2Benign:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glanzmann thrombasthenia

Uncertain:1Benign:1

Benign, reviewed by expert panel	curation	ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	Dec 19, 2023	The NM_000212.3(ITGB3):c.197T>G (p.Leu66Arg) missense variant was observed by Illumina as part of a predisposition screen in an ostensibly healthy population and has been reported in the literature in a blood donor cohort (PMID: 32110192) but has not been reported in a GT patient. There is not consensus among computational evidence as to whether there is an effect on the gene or gene product. The variant occurs at a frequency in gnomAD v4.0.0 of 0.002756 (3252/1180038 alleles) in the European (non-Finnish) population, which is higher than the ClinGen PD VCEP BA1 threshold (>0.0024), and therefore meets this criterion (BA1). In summary this variant meets criteria for classification as Benign for Glanzmann thrombasthenia. GT-specific criteria applied: BA1. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Thrombocytopenia;C1458140:Abnormal bleeding

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Birmingham Platelet Group; University of Birmingham

May 01, 2020

- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 30, 2024

Variant summary: ITGB3 c.197T>G (p.Leu66Arg) results in a non-conservative amino acid change located in the PSI domain (IPR016201) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0018 in 282772 control chromosomes, predominantly at a frequency of 0.0037 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in ITGB3 causing Glanzmann Thrombasthenia 2 phenotype. To our knowledge, no occurrence of c.197T>G in individuals affected with Glanzmann Thrombasthenia 2 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 695335). Based on the evidence outlined above, the variant was classified as benign. -

ITGB3-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 24, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Pathogenic

0.38

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.76

D;.

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.54

T;T

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.023

T;T

MetaSVM

Uncertain

0.60

MutationAssessor

Uncertain

2.3

M;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-2.2

N;.

Sift

Benign

0.088

T;.

Sift4G

Benign

0.58

T;T

Polyphen

1.0

D;.

Vest4

0.68

MVP

0.97

MPC

1.5

ClinPred

0.014

GERP RS

5.9

Varity_R

0.56

gMVP

0.95

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