rs483353048
Positions:
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 donor 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. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 30)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
SLC26A4
NM_000441.2 splice_donor_region, intron
NM_000441.2 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.9998
2
Clinical Significance
Conservation
PhyloP100: 2.82
Genes affected
SLC26A4 (HGNC:8818): (solute carrier family 26 member 4) Mutations in this gene are associated with Pendred syndrome, the most common form of syndromic deafness, an autosomal-recessive disease. It is highly homologous to the SLC26A3 gene; they have similar genomic structures and this gene is located 3' of the SLC26A3 gene. The encoded protein has homology to sulfate transporters. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 7-107675112-A-C is Pathogenic according to our data. Variant chr7-107675112-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 133301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SLC26A4 | NM_000441.2 | c.765+3A>C | splice_donor_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_donor_region_variant, intron_variant | NM_000441.2 | ENSP00000494017 | P1 |
Frequencies
GnomAD3 genomes Cov.: 30
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 exome
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3
AN:
1461280
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30
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2
AN XY:
726968
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GnomAD4 genome Cov.: 30
GnomAD4 genome
Cov.:
30
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
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:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -3
Find out detailed SpliceAI scores and Pangolin per-transcript scores at