17-47253901-G-A

Position:

• chr17-47253901-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BA1 BP4

This summary comes from the ClinGen Evidence Repository: The c.40G>A; p.Val14Met missense variant has not been reported in the literature to our knowledge. It is present in an African population at an allele frequency of 0.03606. Computational evidence suggests no impact on the gene or gene product with a REVEL score of 0.115. In summary, this variant meets criteria to be classified as benign for GT. GT-specific criteria applied: BA1 and BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8622831/MONDO:0010119/011

• Frequency:
  • Genomes: 𝑓 0.010 (24 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (27 hom.)
• Consequence: ITGB3 NM_000212.3 missense
• Clinical Significance: Benign reviewed by expert panel B:4
• Conservation: PhyloP100: 0.0650

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 -9 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGB3	NM_000212.3	c.40G>A	p.Val14Met	missense_variant	1/15	ENST00000559488.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGB3	ENST00000559488.7	c.40G>A	p.Val14Met	missense_variant	1/15	1	NM_000212.3	P1
ITGB3	ENST00000571680.1	c.40G>A	p.Val14Met	missense_variant	1/9	1
ITGB3	ENST00000696963.1	c.40G>A	p.Val14Met	missense_variant	1/14

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1561 AN: 151838 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.0362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000177

Gnomad OTH AF: 0.00479

GnomAD3 exomes AF: 0.000841 AC: 62 AN: 73718 Hom.: 0 AF XY: 0.000696 AC XY: 30 AN XY: 43080

Gnomad AFR exome AF: 0.0341

Gnomad AMR exome AF: 0.000710

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000244

Gnomad OTH exome AF: 0.000986

GnomAD4 exome AF: 0.00100 AC: 1247 AN: 1242408 Hom.: 27 Cov.: 30 AF XY: 0.000881 AC XY: 538 AN XY: 610550

Gnomad4 AFR exome AF: 0.0397

Gnomad4 AMR exome AF: 0.000838

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000134

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000840

Gnomad4 OTH exome AF: 0.00193

GnomAD4 genome AF: 0.0103 AC: 1559 AN: 151946 Hom.: 24 Cov.: 32 AF XY: 0.00999 AC XY: 742 AN XY: 74306

Gnomad4 AFR AF: 0.0361

Gnomad4 AMR AF: 0.00249

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000177

Gnomad4 OTH AF: 0.00474

Alfa AF: 0.00586 Hom.: 2

Bravo AF: 0.0118

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0207 AC: 69

ESP6500EA AF: 0.000429 AC: 3

ExAC AF: 0.00170 AC: 168

Asia WGS AF: 0.00203 AC: 7 AN: 3468

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: reviewed by expert panel

Submissions by phenotype

Glanzmann thrombasthenia Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, reviewed by expert panel	curation	ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	Jun 04, 2020	The c.40G>A; p.Val14Met missense variant has not been reported in the literature to our knowledge. It is present in an African population at an allele frequency of 0.03606. Computational evidence suggests no impact on the gene or gene product with a REVEL score of 0.115. In summary, this variant meets criteria to be classified as benign for GT. GT-specific criteria applied: BA1 and BP4. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 25, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	17
DANN	Benign	0.95
DEOGEN2	Benign	0.32	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.74	T;T
MetaRNN	Benign	0.0024	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.46	N;.
Sift	Uncertain	0.028	D;.
Sift4G	Uncertain	0.042	D;D
Polyphen		0.026	B;.
Vest4		0.23
MVP		0.66
MPC		0.42
ClinPred		0.013	T
GERP RS		-2.7
Varity_R		0.062
gMVP		0.48

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: rs115600591; hg19: chr17-45331267;