NM_002203.4:c.1600G>A

Variant names:

• chr5-53062927-G-A
• rs1801106
• NM_002203.4:c.1600G>A

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.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. 16/21 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:3
• Conservation: PhyloP100: 3.00
• Publications: 28 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 (MetaRNN=0.0011746883).
• BP6: Variant 5-53062927-G-A is Benign according to our data. Variant chr5-53062927-G-A is described in CliVar as Benign. Clinvar id is 353753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-53062927-G-A is described in CliVar as Benign. Clinvar id is 353753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-53062927-G-A is described in CliVar 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 rank	MANE	Protein	UniProt
ITGA2	NM_002203.4	c.1600G>A	p.Glu534Lys	missense_variant, splice_region_variant	Exon 13 of 30	ENST00000296585.10	NP_002194.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITGA2	ENST00000296585.10	c.1600G>A	p.Glu534Lys	missense_variant, splice_region_variant	Exon 13 of 30	1	NM_002203.4	ENSP00000296585.5

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

GnomAD2 exomes AF: 0.0856 AC: 20898 AN: 244036 AF XY: 0.0867

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 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

African (AFR) AF: 0.193 AC: 6340 AN: 32862

American (AMR) AF: 0.0621 AC: 2712 AN: 43658

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 2968 AN: 25796

East Asian (EAS) AF: 0.0338 AC: 1330 AN: 39324

South Asian (SAS) AF: 0.0896 AC: 7600 AN: 84826

European-Finnish (FIN) AF: 0.0531 AC: 2814 AN: 52982

Middle Eastern (MID) AF: 0.153 AC: 870 AN: 5680

European-Non Finnish (NFE) AF: 0.0876 AC: 96716 AN: 1103902

Other (OTH) AF: 0.0956 AC: 5705 AN: 59650

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

African (AFR) AF: 0.188 AC: 7670 AN: 40796

American (AMR) AF: 0.0849 AC: 1277 AN: 15046

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 386 AN: 3448

East Asian (EAS) AF: 0.0269 AC: 136 AN: 5048

South Asian (SAS) AF: 0.0873 AC: 415 AN: 4756

European-Finnish (FIN) AF: 0.0587 AC: 576 AN: 9820

Middle Eastern (MID) AF: 0.168 AC: 49 AN: 292

European-Non Finnish (NFE) AF: 0.0903 AC: 6077 AN: 67290

Other (OTH) AF: 0.125 AC: 259 AN: 2068

Alfa AF: 0.0938 Hom.: 2661

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 10, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

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
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
PhyloP100		3.0
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
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1801106; hg19: chr5-52358757;