rs74458693

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP3_ModeratePP5_Very_Strong

The NM_000212.3(ITGB3):c.1260G>A(p.Thr420=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

ITGB3
NM_000212.3 splice_region, synonymous

Scores

Splicing: ADA: 0.9999

Clinical Significance

Likely pathogenic reviewed by expert panel P:2

Conservation

PhyloP100: 2.51

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 17-47291088-G-A is Pathogenic according to our data. Variant chr17-47291088-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 996184.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGB3	NM_000212.3 linkuse as main transcript	c.1260G>A	p.Thr420=	splice_region_variant, synonymous_variant	9/15	ENST00000559488.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGB3	ENST00000559488.7 linkuse as main transcript	c.1260G>A	p.Thr420=	splice_region_variant, synonymous_variant	9/15	1	NM_000212.3	P1	P05106-1
ITGB3	ENST00000571680.1 linkuse as main transcript	c.1260G>A	p.Thr420=	synonymous_variant	9/9	1
ITGB3	ENST00000573377.1 linkuse as main transcript	c.36G>A	p.Thr12=	synonymous_variant, NMD_transcript_variant	1/2	1
ITGB3	ENST00000696963.1 linkuse as main transcript	c.1260G>A	p.Thr420=	splice_region_variant, synonymous_variant	9/14				P05106-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251392

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135860

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461810

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727194

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000496

Hom.:

Bravo

AF:

0.00000378

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glanzmann thrombasthenia

Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

Nov 02, 2023

The ITGB3 synonymous variant NM_000212.3:c.1260G>A is predicted to lead to loss of the adjacent canonical splice donor and in vitro minigene assays and sequence analysis of patient mRNA suggest the variant results in the in frame deletion of exon 9 (PMID: 8878424; PM4). This variant has been observed in homozygosity in two individuals (Patient RS in PMID: 8878424 and GT50 in PMID: 25728920; PM3), at least one of which was reported to have a phenotype specific for Glanzmann's thrombasthenia (PMID: 25728920, GT50; PP4_moderate). Furthermore, the variant is rare in control population databases (MAF<1/10,000; PM2_supporting). In summary, this variant meets criteria to be classified as likely pathogenic for GT. GT-specific criteria applied: PM3, PM4, PM2_supporting, PP3, PP4_moderate. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 29, 2023

This sequence change affects codon 420 of the ITGB3 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the ITGB3 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs74458693, gnomAD 0.004%). This variant has been observed in individuals with autosomal recessive Glanzmann thrombasthenia (PMID: 8878424, 25728920, 30138987). This variant is also known as position 20624G>A. ClinVar contains an entry for this variant (Variation ID: 996184). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 9 and activation of a cryptic splice site and introduces a premature termination codon (PMID: 8878424). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.31

Cadd

Uncertain

Dann

Benign

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.78

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.36

Position offset: 5

DS_DL_spliceai

0.78

Position offset: 0

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over