NM_000212.3:c.1545G>A

Variant names:

• chr17-47292423-G-A
• rs4634
• NM_000212.3:c.1545G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP7 BA1 BP4

This summary comes from the ClinGen Evidence Repository: After a comprehensive literature search of the synonymous variant NM_000212.3(ITGB3):c.1545G>A (p.Arg515=), no individuals with Glanzmann thrombasthenia were reported with the variant. Moreover, the variant has a minor allele frequency of 0.3455 (6891/19946 alleles) in gnomAD, found in the East Asian population, which is considerably higher than the expected frequency of the disease(BA1). In silico predictor spliceAI revealed that the synonymous mutation is not expected to impact splicing and a PhyloP score of 0.285 shows that the nucleotide position is not highly conserved (BP4, BP7). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BA1, BP4, BP7 (PD VCEP specifications version 2.1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8623284/MONDO:0100326/011

• Frequency:
  • Genomes: 𝑓 0.29 (6387 hom., cov: 33)
  • Exomes 𝑓: 0.29 (61521 hom.)
• Consequence: ITGB3 NM_000212.3 synonymous
• Clinical Significance: Benign reviewed by expert panel B:9
• Conservation: PhyloP100: 0.237
• Publications: 29 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

Specifications for ITGB3 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGB3	NM_000212.3	MANE Select	c.1545G>A	p.Arg515Arg	synonymous	Exon 10 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.1545G>A	p.Arg515Arg	synonymous	Exon 10 of 15	ENSP00000452786.2	P05106-1
	ENSG00000259753	ENST00000560629.1	TSL:2	n.1509G>A		non_coding_transcript_exon	Exon 10 of 18	ENSP00000456711.2	H3BM21
	ITGB3	ENST00000696963.1		c.1545G>A	p.Arg515Arg	synonymous	Exon 10 of 14	ENSP00000513002.1	P05106-2

Frequencies

GnomAD3 genomes AF: 0.286 AC: 43520 AN: 152040 Hom.: 6378 Cov.: 33

Gnomad AFR AF: 0.265

Gnomad AMI AF: 0.266

Gnomad AMR AF: 0.280

Gnomad ASJ AF: 0.282

Gnomad EAS AF: 0.332

Gnomad SAS AF: 0.295

Gnomad FIN AF: 0.283

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.297

Gnomad OTH AF: 0.306

GnomAD2 exomes AF: 0.286 AC: 71672 AN: 250356 AF XY: 0.289

Gnomad AFR exome AF: 0.266

Gnomad AMR exome AF: 0.230

Gnomad ASJ exome AF: 0.291

Gnomad EAS exome AF: 0.345

Gnomad FIN exome AF: 0.291

Gnomad NFE exome AF: 0.294

Gnomad OTH exome AF: 0.292

GnomAD4 exome AF: 0.289 AC: 422143 AN: 1458868 Hom.: 61521 Cov.: 38 AF XY: 0.289 AC XY: 209879 AN XY: 725170

African (AFR) AF: 0.274 AC: 9152 AN: 33440

American (AMR) AF: 0.235 AC: 10506 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.288 AC: 7510 AN: 26050

East Asian (EAS) AF: 0.341 AC: 13532 AN: 39630

South Asian (SAS) AF: 0.294 AC: 25340 AN: 86190

European-Finnish (FIN) AF: 0.291 AC: 15486 AN: 53248

Middle Eastern (MID) AF: 0.300 AC: 1726 AN: 5752

European-Non Finnish (NFE) AF: 0.290 AC: 321260 AN: 1109612

Other (OTH) AF: 0.293 AC: 17631 AN: 60268

GnomAD4 genome AF: 0.286 AC: 43552 AN: 152158 Hom.: 6387 Cov.: 33 AF XY: 0.285 AC XY: 21226 AN XY: 74366

African (AFR) AF: 0.265 AC: 11020 AN: 41520

American (AMR) AF: 0.280 AC: 4277 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.282 AC: 979 AN: 3472

East Asian (EAS) AF: 0.333 AC: 1720 AN: 5166

South Asian (SAS) AF: 0.294 AC: 1417 AN: 4824

European-Finnish (FIN) AF: 0.283 AC: 2991 AN: 10586

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.297 AC: 20181 AN: 67988

Other (OTH) AF: 0.303 AC: 639 AN: 2110

Alfa AF: 0.288 Hom.: 3871

Bravo AF: 0.282

Asia WGS AF: 0.337 AC: 1171 AN: 3478

EpiCase AF: 0.297

EpiControl AF: 0.304

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	Glanzmann thrombasthenia (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	6.6
DANN	Benign	0.49
PhyloP100		0.24
Mutation Taster		=100/0	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: rs4634; hg19: chr17-45369789; COSMIC: COSV71383299; COSMIC: COSV71383299;