rs137852906
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PP4_Strong
This summary comes from the ClinGen Evidence Repository: The NM_000419.4:c.1750C>T that leads to Arg584Ter is a nonsense variant that has been reported in several GT patients meeting phenotype criteria in the homozygous as well as compound heterozygous states (PMIDs: 25728920, 28888044, 22250950, 9215749, 29675921). It is reported at a frequency >0.0001 in the combined gnomAD v3 and v2.1.1 datasets. This nonsense variant occurs in exon 17 out of 30 and is predicted to result in NMD. In summary, this variant meets criteria to be classified as pathogenic. GT-specific codes applied: PVS1, PP4_strong. LINK:https://erepo.genome.network/evrepo/ui/classification/CA115834/MONDO:0010119/011
Frequency
Consequence
NM_000419.5 stop_gained, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ITGA2B | NM_000419.5 | c.1750C>T | p.Arg584Ter | stop_gained, splice_region_variant | 17/30 | ENST00000262407.6 | |
ITGA2B | XM_011524749.2 | c.1903C>T | p.Arg635Ter | stop_gained, splice_region_variant | 17/29 | ||
ITGA2B | XM_011524750.2 | c.1903C>T | p.Arg635Ter | stop_gained, splice_region_variant | 17/29 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ITGA2B | ENST00000262407.6 | c.1750C>T | p.Arg584Ter | stop_gained, splice_region_variant | 17/30 | 1 | NM_000419.5 | P1 | |
ITGA2B | ENST00000648408.1 | c.1183C>T | p.Arg395Ter | stop_gained, splice_region_variant | 13/25 | ||||
ITGA2B | ENST00000592462.5 | n.545C>T | splice_region_variant, non_coding_transcript_exon_variant | 6/15 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.0000160 AC: 4AN: 250734Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135786
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461054Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5AN XY: 726830
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Glanzmann thrombasthenia Pathogenic:2
Pathogenic, reviewed by expert panel | curation | ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen | Sep 04, 2020 | The NM_000419.4:c.1750C>T that leads to Arg584Ter is a nonsense variant that has been reported in several GT patients meeting phenotype criteria in the homozygous as well as compound heterozygous states (PMIDs: 25728920, 28888044, 22250950, 9215749, 29675921). It is reported at a frequency >0.0001 in the combined gnomAD v3 and v2.1.1 datasets. This nonsense variant occurs in exon 17 out of 30 and is predicted to result in NMD. In summary, this variant meets criteria to be classified as pathogenic. GT-specific codes applied: PVS1, PP4_strong. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 31, 2023 | This sequence change creates a premature translational stop signal (p.Arg584*) in the ITGA2B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ITGA2B are known to be pathogenic (PMID: 21917754). This variant is present in population databases (rs137852906, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with autosomal recessive Glanzmann’s thrombasthenia (PMID: 1317725, 22190468, 30138987). ClinVar contains an entry for this variant (Variation ID: 2892). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Glanzmann thrombasthenia 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 15, 1992 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at