chr5-53060024-T-C

Variant names:

• chr5-53060024-T-C
• rs2303127
• NM_002203.4:c.1312+12T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 10 publications found

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]

ITGA2 Gene-Disease associations (from GenCC):

• platelet-type bleeding disorder 9

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 353751.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
ITGA2	NM_002203.4	c.1312+12T>C		intron_variant	Intron 11 of 29	ENST00000296585.10	NP_002194.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITGA2	ENST00000296585.10	c.1312+12T>C		intron_variant	Intron 11 of 29	1	NM_002203.4	ENSP00000296585.5

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

GnomAD2 exomes AF: 0.388 AC: 97064 AN: 250468 AF XY: 0.387

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 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

African (AFR) AF: 0.282 AC: 9425 AN: 33368

American (AMR) AF: 0.454 AC: 20239 AN: 44568

Ashkenazi Jewish (ASJ) AF: 0.389 AC: 10126 AN: 26040

East Asian (EAS) AF: 0.358 AC: 14181 AN: 39592

South Asian (SAS) AF: 0.366 AC: 31560 AN: 86202

European-Finnish (FIN) AF: 0.397 AC: 21172 AN: 53336

Middle Eastern (MID) AF: 0.381 AC: 2192 AN: 5748

European-Non Finnish (NFE) AF: 0.402 AC: 446238 AN: 1109878

Other (OTH) AF: 0.390 AC: 23502 AN: 60204

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

African (AFR) AF: 0.283 AC: 11739 AN: 41434

American (AMR) AF: 0.427 AC: 6487 AN: 15190

Ashkenazi Jewish (ASJ) AF: 0.371 AC: 1286 AN: 3468

East Asian (EAS) AF: 0.305 AC: 1559 AN: 5108

South Asian (SAS) AF: 0.352 AC: 1698 AN: 4830

European-Finnish (FIN) AF: 0.395 AC: 4174 AN: 10560

Middle Eastern (MID) AF: 0.357 AC: 105 AN: 294

European-Non Finnish (NFE) AF: 0.400 AC: 27142 AN: 67822

Other (OTH) AF: 0.377 AC: 796 AN: 2110

Alfa AF: 0.392 Hom.: 4041

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

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Platelet-type bleeding disorder 9 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs2303127; hg19: chr5-52355854; COSMIC: COSV56864661;