rs1801106

chr5-53062927-G-Achr5-53062927-G-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.1600G>A(p.Glu534Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0901 in 1,598,154 control chromosomes in the GnomAD database, including 7,290 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1140 hom., cov: 32)
  • Exomes 𝑓: 0.088 (6150 hom.)
• Consequence: ITGA2 NM_002203.4 missense, splice_region
• Scores: Splicing: ADA: 0.00001115
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.00

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 (MetaRNN=0.0011746883).
• BP6: Variant 5-53062927-G-A is Benign according to our data. Variant chr5-53062927-G-A is described in ClinVar as [Benign]. Clinvar id is 353753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.184 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGA2	NM_002203.4	c.1600G>A	p.Glu534Lys	missense_variant, splice_region_variant	13/30	ENST00000296585.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGA2	ENST00000296585.10	c.1600G>A	p.Glu534Lys	missense_variant, splice_region_variant	13/30	1	NM_002203.4	P1

Frequencies

GnomAD3 genomes AF: 0.113 AC: 16833 AN: 149358 Hom.: 1132 Cov.: 32

Gnomad AFR AF: 0.187

Gnomad AMI AF: 0.0385

Gnomad AMR AF: 0.0850

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.0269

Gnomad SAS AF: 0.0873

Gnomad FIN AF: 0.0587

Gnomad MID AF: 0.159

Gnomad NFE AF: 0.0903

Gnomad OTH AF: 0.124

GnomAD3 exomes AF: 0.0856 AC: 20898 AN: 244036 Hom.: 1099 AF XY: 0.0867 AC XY: 11438 AN XY: 131910

Gnomad AFR exome AF: 0.190

Gnomad AMR exome AF: 0.0597

Gnomad ASJ exome AF: 0.114

Gnomad EAS exome AF: 0.0193

Gnomad SAS exome AF: 0.0885

Gnomad FIN exome AF: 0.0540

Gnomad NFE exome AF: 0.0914

Gnomad OTH exome AF: 0.0961

GnomAD4 exome AF: 0.0877 AC: 127055 AN: 1448680 Hom.: 6150 Cov.: 31 AF XY: 0.0883 AC XY: 63645 AN XY: 720734

Gnomad4 AFR exome AF: 0.193

Gnomad4 AMR exome AF: 0.0621

Gnomad4 ASJ exome AF: 0.115

Gnomad4 EAS exome AF: 0.0338

Gnomad4 SAS exome AF: 0.0896

Gnomad4 FIN exome AF: 0.0531

Gnomad4 NFE exome AF: 0.0876

Gnomad4 OTH exome AF: 0.0956

GnomAD4 genome AF: 0.113 AC: 16880 AN: 149474 Hom.: 1140 Cov.: 32 AF XY: 0.109 AC XY: 7943 AN XY: 72770

Gnomad4 AFR AF: 0.188

Gnomad4 AMR AF: 0.0849

Gnomad4 ASJ AF: 0.112

Gnomad4 EAS AF: 0.0269

Gnomad4 SAS AF: 0.0873

Gnomad4 FIN AF: 0.0587

Gnomad4 NFE AF: 0.0903

Gnomad4 OTH AF: 0.125

Alfa AF: 0.0882 Hom.: 1095

Bravo AF: 0.117

TwinsUK AF: 0.0903 AC: 335

ALSPAC AF: 0.0919 AC: 354

ESP6500AA AF: 0.181 AC: 799

ESP6500EA AF: 0.0957 AC: 823

ExAC AF: 0.0875 AC: 10605

Asia WGS AF: 0.0890 AC: 308 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Platelet-type bleeding disorder 9 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 10, 2021

This variant is associated with the following publications: (PMID: 22133774, 7901236, 10744142) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	12
Dann	Benign	0.83
Eigen	Benign	0.00062
Eigen_PC	Benign	0.025
FATHMM_MKL	Benign	0.38	N
MetaRNN	Benign	0.0012	T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.59	N
REVEL	Benign	0.057
Sift	Benign	0.88	T
Sift4G	Benign	1.0	T
Vest4		0.044
MPC		0.19
ClinPred		0.0059	T
GERP RS		4.8
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000011
dbscSNV1_RF	Benign	0.0
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: rs1801106; hg19: chr5-52358757;