rs36080296

chr17-47283385-T-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_000212.3(ITGB3):c.197T>G(p.Leu66Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00236 in 1,614,230 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (9 hom.)
• Consequence: ITGB3 NM_000212.3 missense
• Clinical Significance: Benign reviewed by expert panel U:2 B:2
• Conservation: PhyloP100: 6.25

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02309513).
• BP6: Variant 17-47283385-T-G is Benign according to our data. Variant chr17-47283385-T-G is described in ClinVar as [Benign]. Clinvar id is 695335.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00152 (232/152350) while in subpopulation NFE AF= 0.00251 (171/68034). AF 95% confidence interval is 0.00221. There are 0 homozygotes in gnomad4. There are 111 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGB3	NM_000212.3	c.197T>G	p.Leu66Arg	missense_variant	3/15	ENST00000559488.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGB3	ENST00000559488.7	c.197T>G	p.Leu66Arg	missense_variant	3/15	1	NM_000212.3	P1
ITGB3	ENST00000571680.1	c.197T>G	p.Leu66Arg	missense_variant	3/9	1
ITGB3	ENST00000696963.1	c.197T>G	p.Leu66Arg	missense_variant	3/14

Frequencies

GnomAD3 genomes AF: 0.00152 AC: 232 AN: 152232 Hom.: 0 Cov.: 32

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.: 0 AF XY: 0.00183 AC XY: 248 AN XY: 135856

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.: 9 Cov.: 33 AF XY: 0.00234 AC XY: 1705 AN XY: 727244

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.: 0 Cov.: 32 AF XY: 0.00149 AC XY: 111 AN XY: 74500

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.: 0

Bravo AF: 0.00139

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00244 AC: 21

ExAC AF: 0.00167 AC: 203

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00174

EpiControl AF: 0.00148

ClinVar

Significance: Benign

Submissions summary: Uncertain:2 Benign:2

Revision: reviewed by expert panel

Submissions by phenotype

Glanzmann thrombasthenia Uncertain:1 Benign:1

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. -
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. -

Thrombocytopenia;C1458140:Abnormal bleeding Uncertain:1

Uncertain significance, no assertion criteria provided

research

Birmingham Platelet Group; University of Birmingham

May 01, 2020

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Uncertain	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.54	T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.023	T;T
MetaSVM	Uncertain	0.60	D
MutationAssessor	Uncertain	2.3	M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.59	T
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	T
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

Other links and lift over

dbSNP: rs36080296; hg19: chr17-45360751;