rs111033311
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_000441.2(SLC26A4):c.1264-1G>C variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,460,532 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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_acceptor
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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SLC26A4 | NM_000441.2 | c.1264-1G>C | splice_acceptor_variant | ENST00000644269.2 | NP_000432.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SLC26A4 | ENST00000644269.2 | c.1264-1G>C | splice_acceptor_variant | NM_000441.2 | ENSP00000494017 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250736Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135486
GnomAD4 exome AF: 0.00000753 AC: 11AN: 1460532Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 726626
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Pendred syndrome Pathogenic:4
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Jan 08, 2015 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 30, 2023 | Variant summary: SLC26A4 c.1264-1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 250736 control chromosomes (gnomAD). c.1264-1G>C has been reported in the literature in individuals affected with Pendred Syndrome (example: Pryor_2004, Prasad_2004, and Rodrigues-Paris_2010). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 30, 2023 | This sequence change affects an acceptor splice site in intron 10 of the SLC26A4 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SLC26A4 are known to be pathogenic (PMID: 16283880, 25394566, 26252218, 26445815). This variant is present in population databases (rs111033311, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with Pendred syndrome (PMID: 14679580, 15689455, 19204907). ClinVar contains an entry for this variant (Variation ID: 43500). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | SLC26A4: PVS1, PM2 - |
Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 06, 2023 | - - |
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 15, 2008 | - - |
Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 24, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at