rs786204523
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000441.2(SLC26A4):βc.2127delβ(p.Phe709LeufsTer12) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000161 in 1,612,626 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.0000066 ( 0 hom., cov: 32)
Exomes π: 0.000017 ( 0 hom. )
Consequence
SLC26A4
NM_000441.2 frameshift
NM_000441.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.12
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
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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 7-107710088-CT-C is Pathogenic according to our data. Variant chr7-107710088-CT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188869.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-107710088-CT-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC26A4 | NM_000441.2 | c.2127del | p.Phe709LeufsTer12 | frameshift_variant | 19/21 | ENST00000644269.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC26A4 | ENST00000644269.2 | c.2127del | p.Phe709LeufsTer12 | frameshift_variant | 19/21 | NM_000441.2 | P1 | ||
SLC26A4 | ENST00000644846.1 | c.*29del | 3_prime_UTR_variant, NMD_transcript_variant | 8/10 | |||||
SLC26A4 | ENST00000492030.2 | n.377-64del | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152198Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251278Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135798
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GnomAD4 exome AF: 0.0000171 AC: 25AN: 1460428Hom.: 0 Cov.: 29 AF XY: 0.0000165 AC XY: 12AN XY: 726660
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152198Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74348
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Pendred syndrome Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jul 17, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Jul 08, 2014 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 22, 2022 | 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 (gnomAD); This variant is associated with the following publications: (PMID: 24224479, 33199029, 9618167) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 04, 2024 | This sequence change creates a premature translational stop signal (p.Phe709Leufs*12) 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 (rs558570919, gnomAD 0.002%). This premature translational stop signal has been observed in individuals with Pendred syndrome (PMID: 9618167, 24224479). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 188869). For these reasons, this variant has been classified as Pathogenic. - |
Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 10, 2024 | - - |
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