NM_000212.3:c.346C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3

This summary comes from the ClinGen Evidence Repository: The c.346C>T variant in ITGB3 is a missense variant predicted to cause substitution of Leucine by Phenylalanine at amino acid 116 (p.Leu116Phe). The highest population minor allele frequency in gnomAD v4.0.0 is 0.0003737 (28/74930 alleles) in the African/African American population. This intermediate allele frequency is lower than the ClinGen PD VCEP threshold (>0.00158) for BS1 but higher than the threshold (<0.0001) for PM2_Supporting. The computational predictor REVEL gives a score of 0.773, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). This variant was observed as part of a predisposition screen in an ostensibly healthy population by Illumina. This variant is also reported in ClinVar in a heterozygous, Portuguese female, presenting with autosomal dominant macrothrombocytopenia (Unidade de Genética Molecular, Centro Hospitalar Universitário do Porto; SCV002540771.1). The only case of this variant occurring in autosomal recessive Glanzmann thrombasthenia (PMID:27469266) was in a patient with an alternate explanation for disease, compound heterozygous for c.861del and c.1456del (both classified Pathogenic by the PD-VCEP). In summary, this variant meets the criteria to be classified as VUS for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP3 (VCEP specifications version 2). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8622917/MONDO:0100326/011

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

ITGB3
NM_000212.3 missense

Scores

3
11
4

Clinical Significance

Uncertain significance reviewed by expert panel P:1U:3

Conservation

PhyloP100: 2.75
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PP3
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ITGB3NM_000212.3 linkc.346C>T p.Leu116Phe missense_variant Exon 3 of 15 ENST00000559488.7 NP_000203.2 P05106-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ITGB3ENST00000559488.7 linkc.346C>T p.Leu116Phe missense_variant Exon 3 of 15 1 NM_000212.3 ENSP00000452786.2 P05106-1
ITGB3ENST00000571680.1 linkc.346C>T p.Leu116Phe missense_variant Exon 3 of 9 1 ENSP00000461626.1 I3L4X8
ENSG00000259753ENST00000560629.1 linkn.310C>T non_coding_transcript_exon_variant Exon 3 of 18 2 ENSP00000456711.2 H3BM21
ITGB3ENST00000696963.1 linkc.346C>T p.Leu116Phe missense_variant Exon 3 of 14 ENSP00000513002.1 P05106-2

Frequencies

GnomAD3 genomes
AF:
0.000138
AC:
21
AN:
152194
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000458
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:
0.00
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000320
AC:
8
AN:
250060
Hom.:
0
AF XY:
0.0000222
AC XY:
3
AN XY:
135300
show subpopulations
Gnomad AFR exome
AF:
0.000370
Gnomad AMR exome
AF:
0.00
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:
0.0000178
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000157
AC:
23
AN:
1461874
Hom.:
0
Cov.:
33
AF XY:
0.0000138
AC XY:
10
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.000269
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000989
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.000138
AC:
21
AN:
152194
Hom.:
0
Cov.:
32
AF XY:
0.000108
AC XY:
8
AN XY:
74356
show subpopulations
Gnomad4 AFR
AF:
0.000458
Gnomad4 AMR
AF:
0.0000655
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:
0.000478
Alfa
AF:
0.000125
Hom.:
0
Bravo
AF:
0.000208
ESP6500AA
AF:
0.000681
AC:
3
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000412
AC:
5

ClinVar

Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:3
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Glanzmann thrombasthenia Uncertain:2
Dec 19, 2023
ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen
Significance: Uncertain significance
Review Status: reviewed by expert panel
Collection Method: curation

The c.346C>T variant in ITGB3 is a missense variant predicted to cause substitution of Leucine by Phenylalanine at amino acid 116 (p.Leu116Phe). The highest population minor allele frequency in gnomAD v4.0.0 is 0.0003737 (28/74930 alleles) in the African/African American population. This intermediate allele frequency is lower than the ClinGen PD VCEP threshold (>0.00158) for BS1 but higher than the threshold (<0.0001) for PM2_Supporting. The computational predictor REVEL gives a score of 0.773, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). This variant was observed as part of a predisposition screen in an ostensibly healthy population by Illumina. This variant is also reported in ClinVar in a heterozygous, Portuguese female, presenting with autosomal dominant macrothrombocytopenia (Unidade de Genética Molecular, Centro Hospitalar Universitário do Porto; SCV002540771.1). The only case of this variant occurring in autosomal recessive Glanzmann thrombasthenia (PMID: 27469266) was in a patient with an alternate explanation for disease, compound heterozygous for c.861del and c.1456del (both classified Pathogenic by the PD-VCEP). In summary, this variant meets the criteria to be classified as VUS for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP3 (VCEP specifications version 2). -

Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Bleeding disorder, platelet-type, 24 Pathogenic:1
-
Unidade de Genética Molecular, Centro Hospitalar Universitário do Porto
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: research

PM1, PM2, PP2, PP3, PP1 -

not provided Uncertain:1
Oct 11, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 116 of the ITGB3 protein (p.Leu116Phe). This variant is present in population databases (rs72547409, gnomAD 0.05%). This missense change has been observed in individual(s) with clinical features of Glanzmann thrombasthenia (PMID: 27469266). ClinVar contains an entry for this variant (Variation ID: 890134). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ITGB3 protein function with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.37
BayesDel_addAF
Benign
-0.075
T
BayesDel_noAF
Uncertain
0.040
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.90
D;.
Eigen
Uncertain
0.57
Eigen_PC
Uncertain
0.49
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Benign
0.79
T;T
M_CAP
Uncertain
0.27
D
MetaRNN
Uncertain
0.59
D;D
MetaSVM
Pathogenic
0.99
D
MutationAssessor
Pathogenic
3.0
M;.
PrimateAI
Benign
0.46
T
PROVEAN
Uncertain
-3.1
D;.
Sift
Uncertain
0.026
D;.
Sift4G
Uncertain
0.026
D;D
Polyphen
0.99
D;.
Vest4
0.48
MVP
0.96
MPC
1.3
ClinPred
0.85
D
GERP RS
4.9
Varity_R
0.65
gMVP
0.73

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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.

Other links and lift over

dbSNP: rs72547409; hg19: chr17-45360900; API