17-47307584-C-T

Position:

chr17-47307584-C-T

Variant summary

Our verdict is Pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPP4_Strong

This summary comes from the ClinGen Evidence Repository: The NM_000212.2:c.2248C>T variant is a nonsense variant that results in premature termination of translation; however, NMD is not predicted. The variant is reported at a frequency of 0.0006008 in gnomAD v2.1.1 in the African population and does not meet PM2 or BS1 (PM2 threshold: <0.0001; BS1 threshold >0.00158). The variant is observed in one homozygous and 3 compound heterozygous individuals in the literature and from internal laboratory data (PMID:20106508, 9351872, 30138987); however, evidence from the in-trans variatns is not applicable as Arg750Ter does not meet PM2. Functional evidence from PMID:9351872 shows that the variant-expressing CHO cells bind fibrinogen but fail to spread on fibrinogen-coated surface. In summary, the Arg750Ter variant is classified as pathogenic. GT-specific criteria applied: PVS1_Strong, PP4_Strong. LINK:https://erepo.genome.network/evrepo/ui/classification/CA123246/MONDO:0010119/011

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

ITGB3
ENST00000559488.7 stop_gained

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:7

Conservation

PhyloP100: 3.88

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:

EFCAB13-DT (HGNC:55338): (EFCAB13 divergent transcript)

EFCAB13-DT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 8 ACMG points.

PVS1

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/exons	MANE	Protein
ITGB3	NM_000212.3 linkuse as main transcript	c.2248C>T	p.Arg750Ter	stop_gained	14/15	ENST00000559488.7	NP_000203.2
EFCAB13-DT	NR_110880.1 linkuse as main transcript	n.363-3802G>A		intron_variant, non_coding_transcript_variant
EFCAB13-DT	NR_110881.1 linkuse as main transcript	n.227-3802G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITGB3	ENST00000559488.7 linkuse as main transcript	c.2248C>T	p.Arg750Ter	stop_gained	14/15	1	NM_000212.3	ENSP00000452786	P1	P05106-1
EFCAB13-DT	ENST00000575039.1 linkuse as main transcript	n.227-3802G>A		intron_variant, non_coding_transcript_variant		5
ITGB3	ENST00000696963.1 linkuse as main transcript	c.2248C>T	p.Arg750Ter	stop_gained	14/14			ENSP00000513002		P05106-2

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000437

AC:

AN:

251438

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.000615

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.000478

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.000151

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.000481

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000556

Hom.:

Bravo

AF:

0.000128

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 18, 2022	Nonsense variant predicted to result in protein truncation in a gene for which loss of function is a known mechanism of disease; Also known as c.2268C>T, p.(R724X); This variant is associated with the following publications: (PMID: 25525159, 31589614, 9351872, 20106508, 30138987, 32089034) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	This sequence change creates a premature translational stop signal (p.Arg750*) in the ITGB3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ITGB3 are known to be pathogenic (PMID: 21917754). This variant is present in population databases (rs121918450, gnomAD 0.06%). This premature translational stop signal has been observed in individual(s) with clinical features of autosomal recessive ITGB3-related conditions (PMID: 9351872, 20106508). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 13564). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects ITGB3 function (PMID: 9351872). For these reasons, this variant has been classified as Pathogenic. -

Glanzmann thrombasthenia

Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

Oct 01, 2021

The NM_000212.2:c.2248C>T variant is a nonsense variant that results in premature termination of translation; however, NMD is not predicted. The variant is reported at a frequency of 0.0006008 in gnomAD v2.1.1 in the African population and does not meet PM2 or BS1 (PM2 threshold: <0.0001; BS1 threshold >0.00158). The variant is observed in one homozygous and 3 compound heterozygous individuals in the literature and from internal laboratory data (PMID: 20106508, 9351872, 30138987); however, evidence from the in-trans variatns is not applicable as Arg750Ter does not meet PM2. Functional evidence from PMID: 9351872 shows that the variant-expressing CHO cells bind fibrinogen but fail to spread on fibrinogen-coated surface. In summary, the Arg750Ter variant is classified as pathogenic. GT-specific criteria applied: PVS1_Strong, PP4_Strong. -

Glanzmann thrombasthenia 2

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 1997

- -

Platelet-type bleeding disorder 16

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 10, 2018

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Hyper-IgE recurrent infection syndrome 1, autosomal dominant

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Dec 17, 2024

- -

Glanzmann thrombasthenia 1

Pathogenic:1

Pathogenic, no assertion criteria provided

research

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.63

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.94

MutationTaster

Benign

1.0

A;A;A

Vest4

0.93

GERP RS

5.5

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

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