5-53060024-T-C

Position:

• chr5-53060024-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002203.4(ITGA2):​c.1312+12T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.394 in 1,610,664 control chromosomes in the GnomAD database, including 126,369 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (10284 hom., cov: 32)
  • Exomes 𝑓: 0.40 (116085 hom.)
• Consequence: ITGA2 NM_002203.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.510

Genes affected

ITGA2 (HGNC:6137): (integrin subunit alpha 2) This gene encodes the alpha subunit of a transmembrane receptor for collagens and related proteins. The encoded protein forms a heterodimer with a beta subunit and mediates the adhesion of platelets and other cell types to the extracellular matrix. Loss of the encoded protein is associated with bleeding disorder platelet-type 9. Antibodies against this protein are found in several immune disorders, including neonatal alloimmune thrombocytopenia. This gene is located adjacent to a related alpha subunit gene. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2012]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 5-53060024-T-C is Benign according to our data. Variant chr5-53060024-T-C is described in ClinVar as [Benign]. Clinvar id is 353751.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-53060024-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.418 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITGA2	NM_002203.4	c.1312+12T>C		intron_variant		ENST00000296585.10	NP_002194.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITGA2	ENST00000296585.10	c.1312+12T>C		intron_variant		1	NM_002203.4	ENSP00000296585	P1

Frequencies

GnomAD3 genomes AF: 0.365 AC: 55352 AN: 151610 Hom.: 10285 Cov.: 32

Gnomad AFR AF: 0.283

Gnomad AMI AF: 0.423

Gnomad AMR AF: 0.427

Gnomad ASJ AF: 0.371

Gnomad EAS AF: 0.305

Gnomad SAS AF: 0.352

Gnomad FIN AF: 0.395

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.400

Gnomad OTH AF: 0.377

GnomAD3 exomes AF: 0.388 AC: 97064 AN: 250468 Hom.: 19141 AF XY: 0.387 AC XY: 52377 AN XY: 135394

Gnomad AFR exome AF: 0.285

Gnomad AMR exome AF: 0.458

Gnomad ASJ exome AF: 0.386

Gnomad EAS exome AF: 0.300

Gnomad SAS exome AF: 0.363

Gnomad FIN exome AF: 0.397

Gnomad NFE exome AF: 0.400

Gnomad OTH exome AF: 0.387

GnomAD4 exome AF: 0.397 AC: 578635 AN: 1458936 Hom.: 116085 Cov.: 37 AF XY: 0.396 AC XY: 287207 AN XY: 725874

Gnomad4 AFR exome AF: 0.282

Gnomad4 AMR exome AF: 0.454

Gnomad4 ASJ exome AF: 0.389

Gnomad4 EAS exome AF: 0.358

Gnomad4 SAS exome AF: 0.366

Gnomad4 FIN exome AF: 0.397

Gnomad4 NFE exome AF: 0.402

Gnomad4 OTH exome AF: 0.390

GnomAD4 genome AF: 0.365 AC: 55372 AN: 151728 Hom.: 10284 Cov.: 32 AF XY: 0.365 AC XY: 27064 AN XY: 74138

Gnomad4 AFR AF: 0.283

Gnomad4 AMR AF: 0.427

Gnomad4 ASJ AF: 0.371

Gnomad4 EAS AF: 0.305

Gnomad4 SAS AF: 0.352

Gnomad4 FIN AF: 0.395

Gnomad4 NFE AF: 0.400

Gnomad4 OTH AF: 0.377

Alfa AF: 0.382 Hom.: 2503

Bravo AF: 0.366

Asia WGS AF: 0.335 AC: 1163 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Platelet-type bleeding disorder 9 Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.0
DANN	Benign	0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs2303127; hg19: chr5-52355854; COSMIC: COSV56864661;