Genetic Variant ITGB3:p.Arg6Gly (chr17-47253877-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000212.3(ITGB3):c.16C>G(p.Arg6Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000272 in 1,102,346 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R6Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

ITGB3
NM_000212.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0240

Publications

1 publications found

Variant links:

Genes affected

ITGB3 (HGNC:6156): (integrin subunit beta 3) The ITGB3 protein product is the integrin beta chain beta 3. Integrins are integral cell-surface proteins composed of an alpha chain and a beta chain. A given chain may combine with multiple partners resulting in different integrins. Integrin beta 3 is found along with the alpha IIb chain in platelets. Integrins are known to participate in cell adhesion as well as cell-surface mediated signalling. [provided by RefSeq, Jul 2008]

ITGB3 Gene-Disease associations (from GenCC):

platelet-type bleeding disorder 16
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
Glanzmann thrombasthenia
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Glanzmann thrombasthenia 2
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
bleeding disorder, platelet-type, 24
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
autosomal dominant macrothrombocytopenia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Glanzmann's thrombasthenia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ITGB3 links:

ENSG00000259753 (HGNC:):

ENSG00000259753 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.058508784).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000212.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGB3	NM_000212.3	MANE Select	c.16C>G	p.Arg6Gly	missense	Exon 1 of 15	NP_000203.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ITGB3	ENST00000559488.7	TSL:1 MANE Select	c.16C>G	p.Arg6Gly	missense	Exon 1 of 15	ENSP00000452786.2	P05106-1
ITGB3	ENST00000571680.1	TSL:1	c.16C>G	p.Arg6Gly	missense	Exon 1 of 9	ENSP00000461626.1	I3L4X8
ITGB3	ENST00000696963.1		c.16C>G	p.Arg6Gly	missense	Exon 1 of 14	ENSP00000513002.1	P05106-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000272

AC:

AN:

1102346

Hom.:

Cov.:

AF XY:

0.00000190

AC XY:

AN XY:

527552

show subpopulations

African (AFR)

AF:

0.000132

AC:

AN:

22794

American (AMR)

AF:

0.00

AC:

AN:

9354

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15170

East Asian (EAS)

AF:

0.00

AC:

AN:

26038

South Asian (SAS)

AF:

0.00

AC:

AN:

26526

European-Finnish (FIN)

AF:

0.00

AC:

AN:

23438

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3056

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

932038

Other (OTH)

AF:

0.00

AC:

AN:

43932

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.035

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Benign

0.67

DEOGEN2

Benign

0.31

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0063

LIST_S2

Benign

0.40

M_CAP

Benign

0.022

MetaRNN

Benign

0.059

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PhyloP100

0.024

PrimateAI

Uncertain

0.73

PROVEAN

Benign

0.050

Sift

Benign

0.15

Sift4G

Benign

0.37

Polyphen

0.013

Vest4

0.12

MutPred

0.33

Loss of methylation at R6 (P = 0.018)

MVP

0.71

MPC

0.52

ClinPred

0.062

GERP RS

-2.0

PromoterAI

-0.11

Neutral

(source)

Varity_R

0.064

gMVP

0.73

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over