rs483353048
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_000441.2(SLC26A4):c.765+3A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,280 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000441.2 splice_region, intron
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SLC26A4 | NM_000441.2 | c.765+3A>C | splice_region_variant, intron_variant | ENST00000644269.2 | NP_000432.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SLC26A4 | ENST00000644269.2 | c.765+3A>C | splice_region_variant, intron_variant | NM_000441.2 | ENSP00000494017.1 |
Frequencies
GnomAD3 genomes Cov.: 30
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461280Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2AN XY: 726968
GnomAD4 genome Cov.: 30
ClinVar
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | literature only | Molecular Genetics Laboratory; Baylor College of Medicine | - | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 22, 2023 | This sequence change falls in intron 6 of the SLC26A4 gene. It does not directly change the encoded amino acid sequence of the SLC26A4 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with deafness (PMID: 25991456). 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: 133301). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the c.765+3A nucleotide in the SLC26A4 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 23336812, 31033086). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at