chr5-53051539-C-T

Variant names:

• chr5-53051539-C-T
• rs1126643
• NM_002203.4:c.759C>T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4 BP6_Very_Strong BP7 BA1

The NM_002203.4(ITGA2):​c.759C>T​(p.Phe253Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.391 in 1,611,596 control chromosomes in the GnomAD database, including 124,953 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (10259 hom., cov: 31)
  • Exomes 𝑓: 0.39 (114694 hom.)
• Consequence: ITGA2 NM_002203.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.61

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.15).
• BP6: Variant 5-53051539-C-T is Benign according to our data. Variant chr5-53051539-C-T is described in ClinVar as [Benign]. Clinvar id is 353741.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-53051539-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.61 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.419 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITGA2	NM_002203.4	c.759C>T	p.Phe253Phe	synonymous_variant	Exon 7 of 30	ENST00000296585.10	NP_002194.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITGA2	ENST00000296585.10	c.759C>T	p.Phe253Phe	synonymous_variant	Exon 7 of 30	1	NM_002203.4	ENSP00000296585.5

Frequencies

GnomAD3 genomes AF: 0.365 AC: 55405 AN: 151598 Hom.: 10260 Cov.: 31

Gnomad AFR AF: 0.290

Gnomad AMI AF: 0.422

Gnomad AMR AF: 0.428

Gnomad ASJ AF: 0.365

Gnomad EAS AF: 0.306

Gnomad SAS AF: 0.352

Gnomad FIN AF: 0.396

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.397

Gnomad OTH AF: 0.374

GnomAD3 exomes AF: 0.386 AC: 96856 AN: 250968 Hom.: 19006 AF XY: 0.385 AC XY: 52218 AN XY: 135618

Gnomad AFR exome AF: 0.291

Gnomad AMR exome AF: 0.457

Gnomad ASJ exome AF: 0.378

Gnomad EAS exome AF: 0.300

Gnomad SAS exome AF: 0.362

Gnomad FIN exome AF: 0.396

Gnomad NFE exome AF: 0.397

Gnomad OTH exome AF: 0.384

GnomAD4 exome AF: 0.394 AC: 575320 AN: 1459880 Hom.: 114694 Cov.: 39 AF XY: 0.393 AC XY: 285560 AN XY: 726314

Gnomad4 AFR exome AF: 0.289

Gnomad4 AMR exome AF: 0.453

Gnomad4 ASJ exome AF: 0.380

Gnomad4 EAS exome AF: 0.358

Gnomad4 SAS exome AF: 0.365

Gnomad4 FIN exome AF: 0.396

Gnomad4 NFE exome AF: 0.399

Gnomad4 OTH exome AF: 0.387

GnomAD4 genome AF: 0.365 AC: 55426 AN: 151716 Hom.: 10259 Cov.: 31 AF XY: 0.366 AC XY: 27111 AN XY: 74128

Gnomad4 AFR AF: 0.290

Gnomad4 AMR AF: 0.428

Gnomad4 ASJ AF: 0.365

Gnomad4 EAS AF: 0.305

Gnomad4 SAS AF: 0.352

Gnomad4 FIN AF: 0.396

Gnomad4 NFE AF: 0.397

Gnomad4 OTH AF: 0.375

Alfa AF: 0.387 Hom.: 16648

Bravo AF: 0.366

Asia WGS AF: 0.335 AC: 1165 AN: 3476

EpiCase AF: 0.393

EpiControl AF: 0.386

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

This variant is associated with the following publications: (PMID: 9950439, 22133274, 21672359, 18836731, 14687991, 16513317, 19388931) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Platelet-type bleeding disorder 9 Benign:1

Mar 06, 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	-0.15
CADD	Benign	7.8
DANN	Benign	0.82
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: rs1126643; hg19: chr5-52347369; COSMIC: COSV56856401;