rs5918

Variant names:

• chr17-47283364-T-C
• rs5918
• NM_000212.3:c.176T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BS3 BP2 BP4 BA1

This summary comes from the ClinGen Evidence Repository: The ITGB3 c.176T>C (p.Leu59Pro) missense variant has been reported many times in the literature as an alloantigenic site. This variant has been observed in cis with several other Glanzmann thrombasthenia variants, including the pathogenic c.224del frameshift variant (PMID:25728920). It is present in gnomAD at an overall allele frequency of 0.1223 (and 0.1550 in the non-Finnish European population). Computational evidence suggest no impact on the gene/gene product, with a REVEL score of 0.217. Functional studies in CHO cells have shown no deleterious effect on surface expression or fibrinogen binding (PMID:10727448). In summary, this variant meets criteria to be classified as benign for GT. GT-specific criteria applied: BA1, BS3, BP2, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA123235/MONDO:0010119/011

• Frequency:
  • Genomes: 𝑓 0.13 (1387 hom., cov: 32)
  • Exomes 𝑓: 0.14 (15584 hom.)
• Consequence: ITGB3 NM_000212.3 missense
• Clinical Significance: Benign reviewed by expert panel B:8
• Conservation: PhyloP100: -1.35
• Publications: 329 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 -14 ACMG points.

• BP2: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BS3: For more information check the summary or visit ClinGen Evidence Repository.
• 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGB3	NM_000212.3	MANE Select	c.176T>C	p.Leu59Pro	missense	Exon 3 of 15	NP_000203.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGB3	ENST00000559488.7	TSL:1 MANE Select	c.176T>C	p.Leu59Pro	missense	Exon 3 of 15	ENSP00000452786.2
	ITGB3	ENST00000571680.1	TSL:1	c.176T>C	p.Leu59Pro	missense	Exon 3 of 9	ENSP00000461626.1
	ENSG00000259753	ENST00000560629.1	TSL:2	n.140T>C		non_coding_transcript_exon	Exon 3 of 18	ENSP00000456711.2

Frequencies

GnomAD3 genomes AF: 0.128 AC: 19456 AN: 152154 Hom.: 1387 Cov.: 32

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.149

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.144

Gnomad EAS AF: 0.00634

Gnomad SAS AF: 0.0998

Gnomad FIN AF: 0.133

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.156

Gnomad OTH AF: 0.142

GnomAD2 exomes AF: 0.121 AC: 30400 AN: 251122 AF XY: 0.123

Gnomad AFR exome AF: 0.106

Gnomad AMR exome AF: 0.0767

Gnomad ASJ exome AF: 0.157

Gnomad EAS exome AF: 0.00277

Gnomad FIN exome AF: 0.145

Gnomad NFE exome AF: 0.154

Gnomad OTH exome AF: 0.133

GnomAD4 exome AF: 0.141 AC: 206046 AN: 1461664 Hom.: 15584 Cov.: 34 AF XY: 0.140 AC XY: 101833 AN XY: 727142

African (AFR) AF: 0.108 AC: 3612 AN: 33478

American (AMR) AF: 0.0797 AC: 3564 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.155 AC: 4052 AN: 26130

East Asian (EAS) AF: 0.00338 AC: 134 AN: 39700

South Asian (SAS) AF: 0.0962 AC: 8296 AN: 86252

European-Finnish (FIN) AF: 0.144 AC: 7712 AN: 53400

Middle Eastern (MID) AF: 0.150 AC: 868 AN: 5768

European-Non Finnish (NFE) AF: 0.153 AC: 169759 AN: 1111820

Other (OTH) AF: 0.133 AC: 8049 AN: 60394

GnomAD4 genome AF: 0.128 AC: 19457 AN: 152272 Hom.: 1387 Cov.: 32 AF XY: 0.125 AC XY: 9315 AN XY: 74446

African (AFR) AF: 0.105 AC: 4372 AN: 41538

American (AMR) AF: 0.102 AC: 1566 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.144 AC: 498 AN: 3468

East Asian (EAS) AF: 0.00674 AC: 35 AN: 5194

South Asian (SAS) AF: 0.0990 AC: 478 AN: 4826

European-Finnish (FIN) AF: 0.133 AC: 1414 AN: 10608

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.156 AC: 10619 AN: 68016

Other (OTH) AF: 0.141 AC: 297 AN: 2110

Alfa AF: 0.144 Hom.: 7301

Bravo AF: 0.124

TwinsUK AF: 0.157 AC: 583

ALSPAC AF: 0.150 AC: 580

ESP6500AA AF: 0.107 AC: 470

ESP6500EA AF: 0.152 AC: 1305

ExAC AF: 0.123 AC: 14952

Asia WGS AF: 0.0640 AC: 225 AN: 3478

EpiCase AF: 0.152

EpiControl AF: 0.161

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Glanzmann thrombasthenia (2)
-	-	2	not specified (2)
-	-	1	PL(A1)/(A2) ALLOANTIGEN POLYMORPHISM (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.046
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	1.1
DANN	Benign	0.42
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.034	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.20	N
PhyloP100		-1.3
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.63	N
Sift	Benign	0.32	T
Sift4G	Benign	0.27	T
Polyphen		0.0030	B
Vest4		0.073
MPC		0.66
ClinPred		0.015	T
GERP RS		-12
Varity_R		0.15
gMVP		0.80
Mutation Taster		=94/6	polymorphism (auto)

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: rs5918; hg19: chr17-45360730; COSMIC: COSV71383764; COSMIC: COSV71383764;