5-53073171-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_002203.4(ITGA2):c.2483C>T(p.Thr828Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00105 in 1,611,908 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. T828T) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00070 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0011 ( 3 hom. )

Consequence

ITGA2
NM_002203.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.193

Publications

8 publications found

Variant links:

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

ITGA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.057516247).

BP6

Variant 5-53073171-C-T is Benign according to our data. Variant chr5-53073171-C-T is described in ClinVar as Benign. ClinVar VariationId is 353767.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 106 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITGA2	NM_002203.4 link	c.2483C>T	p.Thr828Met	missense_variant	Exon 20 of 30	ENST00000296585.10	NP_002194.2	P17301

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITGA2	ENST00000296585.10 link	c.2483C>T	p.Thr828Met	missense_variant	Exon 20 of 30	1	NM_002203.4	ENSP00000296585.5		P17301

Frequencies

GnomAD3 genomes

AF:

0.000698

AC:

106

AN:

151830

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000967

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000985

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00124

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.000682

AC:

171

AN:

250710

AF XY:

0.000657

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00107

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00108

Gnomad OTH exome

AF:

0.000982

GnomAD4 exome

AF:

0.00109

AC:

1593

AN:

1459960

Hom.:

Cov.:

AF XY:

0.00106

AC XY:

771

AN XY:

726382

show subpopulations

African (AFR)

AF:

0.000180

AC:

AN:

33368

American (AMR)

AF:

0.00101

AC:

AN:

44618

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26066

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39656

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86222

European-Finnish (FIN)

AF:

0.0000749

AC:

AN:

53384

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00132

AC:

1466

AN:

1110614

Other (OTH)

AF:

0.00114

AC:

AN:

60280

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

153

229

306

382

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

168

224

280

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000698

AC:

106

AN:

151948

Hom.:

Cov.:

AF XY:

0.000687

AC XY:

AN XY:

74246

show subpopulations

African (AFR)

AF:

0.0000964

AC:

AN:

41486

American (AMR)

AF:

0.000984

AC:

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5136

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00124

AC:

AN:

67890

Other (OTH)

AF:

0.00142

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00100

Hom.:

Bravo

AF:

0.000816

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00151

AC:

ExAC

AF:

0.000692

AC:

EpiCase

AF:

0.00104

EpiControl

AF:

0.00172

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

0.086

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.96

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.16

M_CAP

Benign

0.029

MetaRNN

Benign

0.058

MetaSVM

Benign

-1.0

PhyloP100

0.19

PrimateAI

Benign

0.32

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.053

Sift

Benign

0.071

Sift4G

Benign

0.065

Vest4

0.13

MVP

0.81

MPC

0.22

ClinPred

0.018

GERP RS

-0.45

gMVP

0.32

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over