4-2831573-G-C
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate
The NM_001122681.2(SH3BP2):c.1244G>C(p.Arg415Pro) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Consequence
NM_001122681.2 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SH3BP2 | NM_001122681.2 | c.1244G>C | p.Arg415Pro | missense_variant, splice_region_variant | Exon 9 of 13 | ENST00000503393.8 | NP_001116153.1 | |
SH3BP2 | NM_001145856.2 | c.1415G>C | p.Arg472Pro | missense_variant, splice_region_variant | Exon 9 of 13 | NP_001139328.1 | ||
SH3BP2 | NM_001145855.2 | c.1328G>C | p.Arg443Pro | missense_variant, splice_region_variant | Exon 9 of 13 | NP_001139327.1 | ||
SH3BP2 | NM_003023.4 | c.1244G>C | p.Arg415Pro | missense_variant, splice_region_variant | Exon 9 of 13 | NP_003014.3 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Fibrous dysplasia of jaw Pathogenic:2
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This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 415 of the SH3BP2 protein (p.Arg415Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cherubism (PMID: 11381256, 19576004, 28721660). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7550). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SH3BP2 function (PMID: 22153077). This variant disrupts the p.Arg415 amino acid residue in SH3BP2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11381256, 21045962, 22795151, 24382142, 24608212, 26064398, 28644570; 30236129)). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at