17-47283385-T-G

Variant names:

• chr17-47283385-T-G
• rs36080296
• NM_000212.3:c.197T>G

Variant summary

Our verdict is Benign. The variant received -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
• Clinical Significance: Benign reviewed by expert panel U:2 B:4
• Conservation: PhyloP100: 6.25
• Publications: 13 publications found

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]

ENSG00000259753 (HGNC:):

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

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000212.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGB3	NM_000212.3	MANE Select	c.197T>G	p.Leu66Arg	missense	Exon 3 of 15	NP_000203.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGB3	ENST00000559488.7	TSL:1 MANE Select	c.197T>G	p.Leu66Arg	missense	Exon 3 of 15	ENSP00000452786.2	P05106-1
	ITGB3	ENST00000571680.1	TSL:1	c.197T>G	p.Leu66Arg	missense	Exon 3 of 9	ENSP00000461626.1	I3L4X8
	ENSG00000259753	ENST00000560629.1	TSL:2	n.161T>G		non_coding_transcript_exon	Exon 3 of 18	ENSP00000456711.2	H3BM21

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

GnomAD2 exomes AF: 0.00177 AC: 444 AN: 251368 AF XY: 0.00183

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 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

African (AFR) AF: 0.000299 AC: 10 AN: 33478

American (AMR) AF: 0.00127 AC: 57 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00169 AC: 146 AN: 86256

European-Finnish (FIN) AF: 0.00374 AC: 200 AN: 53418

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00277 AC: 3081 AN: 1112004

Other (OTH) AF: 0.00137 AC: 83 AN: 60396

GnomAD4 genome AF: 0.00152 AC: 232 AN: 152350 Hom.: 0 Cov.: 32 AF XY: 0.00149 AC XY: 111 AN XY: 74500

African (AFR) AF: 0.000385 AC: 16 AN: 41582

American (AMR) AF: 0.000719 AC: 11 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5194

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4824

European-Finnish (FIN) AF: 0.00216 AC: 23 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00251 AC: 171 AN: 68034

Other (OTH) AF: 0.00190 AC: 4 AN: 2106

Alfa AF: 0.00215 Hom.: 2

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

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	1	Glanzmann thrombasthenia (2)
-	-	1	ITGB3-related disorder (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	1	-	Thrombocytopenia;C1458140:Abnormal bleeding (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.023	T
MetaSVM	Uncertain	0.60	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		6.3
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.2	N
Sift	Benign	0.088	T
Sift4G	Benign	0.58	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
Mutation Taster		=15/85	disease causing

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

Other links and lift over

dbSNP: rs36080296; hg19: chr17-45360751;