chr17-44374686-C-T

Variant names:

• chr17-44374686-C-T
• rs5913
• NM_000419.5:c.2916G>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: The c.2916G>A; p.Pro972= synonymous variant has not been reported in the literature to our knowledge. It is present in a non-Finnish European control population at an allele frequency of 0.005351 and no splice impact is predicted. In summary, this variant meets criteria to be classified as benign for GT. GT-specific criteria applied: BA1, BP4, and BP7. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8602530/MONDO:0010119/011

• Frequency:
  • Genomes: 𝑓 0.0034 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (22 hom.)
• Consequence: ITGA2B NM_000419.5 synonymous
• Clinical Significance: Benign reviewed by expert panel B:6
• Conservation: PhyloP100: -0.432
• Publications: 7 publications found

Genes affected

ITGA2B (HGNC:6138): (integrin subunit alpha 2b) This gene encodes a member of the integrin alpha chain family of proteins. The encoded preproprotein is proteolytically processed to generate light and heavy chains that associate through disulfide linkages to form a subunit of the alpha-IIb/beta-3 integrin cell adhesion receptor. This receptor plays a crucial role in the blood coagulation system, by mediating platelet aggregation. Mutations in this gene are associated with platelet-type bleeding disorders, which are characterized by a failure of platelet aggregation, including Glanzmann thrombasthenia. [provided by RefSeq, Jan 2016]

ITGA2B Gene-Disease associations (from GenCC):

• platelet-type bleeding disorder 16

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Glanzmann thrombasthenia

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Glanzmann's thrombasthenia

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• Glanzmann thrombasthenia 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• autosomal dominant macrothrombocytopenia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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_000419.5. 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
	ITGA2B	NM_000419.5	MANE Select	c.2916G>A	p.Pro972Pro	synonymous	Exon 28 of 30	NP_000410.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGA2B	ENST00000262407.6	TSL:1 MANE Select	c.2916G>A	p.Pro972Pro	synonymous	Exon 28 of 30	ENSP00000262407.5
	ITGA2B	ENST00000648408.1		c.2346G>A	p.Pro782Pro	synonymous	Exon 24 of 25	ENSP00000498119.1
	ITGA2B	ENST00000592462.5	TSL:5	n.2427G>A		non_coding_transcript_exon	Exon 15 of 15

Frequencies

GnomAD3 genomes AF: 0.00338 AC: 514 AN: 152080 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00210

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00634

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00291 AC: 729 AN: 250896 AF XY: 0.00305

Gnomad AFR exome AF: 0.000864

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.000398

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000556

Gnomad NFE exome AF: 0.00550

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00470 AC: 6863 AN: 1461676 Hom.: 22 Cov.: 31 AF XY: 0.00459 AC XY: 3339 AN XY: 727142

African (AFR) AF: 0.000866 AC: 29 AN: 33478

American (AMR) AF: 0.00143 AC: 64 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000344 AC: 9 AN: 26134

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

South Asian (SAS) AF: 0.000406 AC: 35 AN: 86256

European-Finnish (FIN) AF: 0.000731 AC: 39 AN: 53366

Middle Eastern (MID) AF: 0.00676 AC: 39 AN: 5768

European-Non Finnish (NFE) AF: 0.00581 AC: 6458 AN: 1111866

Other (OTH) AF: 0.00315 AC: 190 AN: 60386

GnomAD4 genome AF: 0.00338 AC: 514 AN: 152198 Hom.: 4 Cov.: 32 AF XY: 0.00285 AC XY: 212 AN XY: 74400

African (AFR) AF: 0.000866 AC: 36 AN: 41548

American (AMR) AF: 0.00209 AC: 32 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4812

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00634 AC: 431 AN: 67986

Other (OTH) AF: 0.00427 AC: 9 AN: 2110

Alfa AF: 0.00433 Hom.: 1

Bravo AF: 0.00355

EpiCase AF: 0.00703

EpiControl AF: 0.00646

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	Glanzmann thrombasthenia (3)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	4.8
DANN	Benign	0.75
PhyloP100		-0.43
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs5913; hg19: chr17-42452054;