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
Consequence
NM_000212.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ITGB3 | ENST00000559488.7 | c.346C>T | p.Leu116Phe | missense_variant | Exon 3 of 15 | 1 | NM_000212.3 | ENSP00000452786.2 | ||
ITGB3 | ENST00000571680.1 | c.346C>T | p.Leu116Phe | missense_variant | Exon 3 of 9 | 1 | ENSP00000461626.1 | |||
ENSG00000259753 | ENST00000560629.1 | n.310C>T | non_coding_transcript_exon_variant | Exon 3 of 18 | 2 | ENSP00000456711.2 | ||||
ITGB3 | ENST00000696963.1 | c.346C>T | p.Leu116Phe | missense_variant | Exon 3 of 14 | ENSP00000513002.1 |
Frequencies
GnomAD3 genomes AF: 0.000138 AC: 21AN: 152194Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000320 AC: 8AN: 250060Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135300
GnomAD4 exome AF: 0.0000157 AC: 23AN: 1461874Hom.: 0 Cov.: 33 AF XY: 0.0000138 AC XY: 10AN XY: 727240
GnomAD4 genome AF: 0.000138 AC: 21AN: 152194Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8AN XY: 74356
ClinVar
Submissions by phenotype
Glanzmann thrombasthenia Uncertain:2
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). -
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
PM1, PM2, PP2, PP3, PP1 -
not provided Uncertain:1
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at