5-53083447-C-T

Variant names:

• chr5-53083447-C-T
• rs2303122
• NM_002203.4:c.3252C>T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_002203.4(ITGA2):​c.3252C>T​(p.Phe1084Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.363 in 1,565,140 control chromosomes in the GnomAD database, including 104,383 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (9326 hom., cov: 32)
  • Exomes 𝑓: 0.36 (95057 hom.)
• Consequence: ITGA2 NM_002203.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0620

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 5-53083447-C-T is Benign according to our data. Variant chr5-53083447-C-T is described in ClinVar as [Benign]. Clinvar id is 353779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-53083447-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.062 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.404 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITGA2	NM_002203.4	c.3252C>T	p.Phe1084Phe	synonymous_variant	Exon 27 of 30	ENST00000296585.10	NP_002194.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITGA2	ENST00000296585.10	c.3252C>T	p.Phe1084Phe	synonymous_variant	Exon 27 of 30	1	NM_002203.4	ENSP00000296585.5

Frequencies

GnomAD3 genomes AF: 0.349 AC: 52932 AN: 151844 Hom.: 9322 Cov.: 32

Gnomad AFR AF: 0.286

Gnomad AMI AF: 0.408

Gnomad AMR AF: 0.412

Gnomad ASJ AF: 0.341

Gnomad EAS AF: 0.314

Gnomad SAS AF: 0.347

Gnomad FIN AF: 0.395

Gnomad MID AF: 0.341

Gnomad NFE AF: 0.368

Gnomad OTH AF: 0.356

GnomAD3 exomes AF: 0.368 AC: 92207 AN: 250718 Hom.: 17274 AF XY: 0.367 AC XY: 49676 AN XY: 135476

Gnomad AFR exome AF: 0.287

Gnomad AMR exome AF: 0.445

Gnomad ASJ exome AF: 0.352

Gnomad EAS exome AF: 0.309

Gnomad SAS exome AF: 0.355

Gnomad FIN exome AF: 0.395

Gnomad NFE exome AF: 0.366

Gnomad OTH exome AF: 0.356

GnomAD4 exome AF: 0.365 AC: 515459 AN: 1413180 Hom.: 95057 Cov.: 26 AF XY: 0.365 AC XY: 257491 AN XY: 706164

Gnomad4 AFR exome AF: 0.285

Gnomad4 AMR exome AF: 0.440

Gnomad4 ASJ exome AF: 0.354

Gnomad4 EAS exome AF: 0.365

Gnomad4 SAS exome AF: 0.357

Gnomad4 FIN exome AF: 0.392

Gnomad4 NFE exome AF: 0.364

Gnomad4 OTH exome AF: 0.361

GnomAD4 genome AF: 0.348 AC: 52951 AN: 151960 Hom.: 9326 Cov.: 32 AF XY: 0.351 AC XY: 26052 AN XY: 74246

Gnomad4 AFR AF: 0.285

Gnomad4 AMR AF: 0.412

Gnomad4 ASJ AF: 0.341

Gnomad4 EAS AF: 0.314

Gnomad4 SAS AF: 0.347

Gnomad4 FIN AF: 0.395

Gnomad4 NFE AF: 0.368

Gnomad4 OTH AF: 0.356

Alfa AF: 0.360 Hom.: 23255

Bravo AF: 0.348

Asia WGS AF: 0.334 AC: 1162 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 13, 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	-0.39
CADD	Benign	0.81
DANN	Benign	0.50
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs2303122; hg19: chr5-52379277; COSMIC: COSV56857327;