rs786204421
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000441.2(SLC26A4):c.279del(p.Ser93ArgfsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,614,130 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000075 ( 0 hom. )
Consequence
SLC26A4
NM_000441.2 frameshift
NM_000441.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.500
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 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 7-107663409-GT-G is Pathogenic according to our data. Variant chr7-107663409-GT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188715.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-107663409-GT-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC26A4 | NM_000441.2 | c.279del | p.Ser93ArgfsTer4 | frameshift_variant | 3/21 | ENST00000644269.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC26A4 | ENST00000644269.2 | c.279del | p.Ser93ArgfsTer4 | frameshift_variant | 3/21 | NM_000441.2 | P1 | ||
SLC26A4 | ENST00000440056.1 | c.279del | p.Ser93ArgfsTer4 | frameshift_variant | 3/4 | 4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152174Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251460Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135906
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GnomAD4 exome AF: 0.00000752 AC: 11AN: 1461838Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 727226
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GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152292Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74462
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Pendred syndrome Pathogenic:4
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2008 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Mar 06, 2014 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | May 23, 2021 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | This sequence change creates a premature translational stop signal (p.Ser93Argfs*4) in the SLC26A4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC26A4 are known to be pathogenic (PMID: 16283880, 25394566, 26252218, 26445815). This variant is present in population databases (rs786204421, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with Pendred syndrome (PMID: 9920104, 11716048, 23273637). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 188715). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 22, 2021 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 11317356, 11716048, 23273637, 18285825, 14679580, 17940114, 31589614, 9920104, 26752218) - |
not specified Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 09, 2017 | - - |
Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 07, 2023 | - - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at