rs74458693

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP4_ModeratePP3PM2_SupportingPM3PM4

This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8623200/MONDO:0010119/011

Frequency

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

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

ITGB3
NM_000212.3 splice_region, synonymous

Scores

2

Splicing: ADA: 0.9999

2

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:

ENSG00000259753 (HGNC:):

ENSG00000259753 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PM3

For more information check the summary or visit ClinGen Evidence Repository.

PM4

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITGB3	NM_000212.3 link	c.1260G>A	p.Thr420Thr	splice_region_variant, synonymous_variant	Exon 9 of 15	ENST00000559488.7	NP_000203.2	P05106-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITGB3	ENST00000559488.7 link	c.1260G>A	p.Thr420Thr	splice_region_variant, synonymous_variant	Exon 9 of 15	1	NM_000212.3	ENSP00000452786.2		P05106-1
ENSG00000259753	ENST00000560629.1 link	n.1224G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 9 of 18	2		ENSP00000456711.2		H3BM21

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

1

AN:

152170

Hom.:

0

Cov.:

32

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:

3

AN:

251392

Hom.:

0

AF XY:

0.0000221

AC XY:

3

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:

8

AN:

1461810

Hom.:

0

Cov.:

32

AF XY:

0.00000963

AC XY:

7

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:

1

AN:

152170

Hom.:

0

Cov.:

32

AF XY:

0.00

AC XY:

0

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.:

0

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

Nov 02, 2023

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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

Jul 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 altered 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 produces a non-functional protein and/or introduces a premature termination codon (PMID: 8878424). 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

25

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.

Other links and lift over

dbSNP: rs74458693; hg19: chr17-45368454; COSMIC: COSV101457669;