7-107704355-G-T
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP4
The NM_000441.2(SLC26A4):c.2059G>T(p.Asp687Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000657 in 1,399,428 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000441.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SLC26A4 | ENST00000644269.2 | c.2059G>T | p.Asp687Tyr | missense_variant | Exon 18 of 21 | NM_000441.2 | ENSP00000494017.1 | |||
SLC26A4 | ENST00000492030.2 | n.346G>T | non_coding_transcript_exon_variant | Exon 3 of 6 | 5 | |||||
SLC26A4 | ENST00000644846.1 | n.744+2298G>T | intron_variant | Intron 7 of 9 | ENSP00000494344.1 |
Frequencies
GnomAD3 genomes AF: 0.000368 AC: 56AN: 152142Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000746 AC: 17AN: 227856Hom.: 1 AF XY: 0.0000897 AC XY: 11AN XY: 122586
GnomAD4 exome AF: 0.0000289 AC: 36AN: 1247170Hom.: 1 Cov.: 19 AF XY: 0.0000207 AC XY: 13AN XY: 629090
GnomAD4 genome AF: 0.000368 AC: 56AN: 152258Hom.: 0 Cov.: 32 AF XY: 0.000443 AC XY: 33AN XY: 74440
ClinVar
Submissions by phenotype
Pendred syndrome Uncertain:3
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not specified Uncertain:2
Variant classified as Uncertain Significance - Favor Pathogenic. The Asp687Tyr v ariant in SLC26A4 has not been previously identified by our laboratory. One stud y has shown that the Asp687Tyr variant impacts protein function (Dossena 2011). Computational analyses (biochemical amino acid properties, conservation, AlignGV GD, PolyPhen2, and SIFT) also suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Th is variant has been identified in 0.1% (6/4376) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.was hington.edu/EVS/; dbSNP rs35548413); however, this frequency is not high enough to rule out a pathogenic role. In summary, the clinical significance of this var iant cannot be determined with certainty; however, based upon the functional dat a, we would lean towards a more likely pathogenic role. -
Variant summary: SLC26A4 c.2059G>T (p.Asp687Tyr) results in a non-conservative amino acid change located in the STAS domain (IPR002645) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.5e-05 in 227856 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in SLC26A4 causing Pendred Syndrome (7.5e-05 vs 0.0035), allowing no conclusion about variant significance. c.2059G>T has been reported in the literature in at-least one individual affected with non-syndromic hearing loss, without strong evidence for causality (Perry_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Pendred Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in about 60% of normal activity in HEK 293 cells (Dossena_2011). The following publications have been ascertained in the context of this evaluation (PMID: 22116359, 36515421). ClinVar contains an entry for this variant (Variation ID: 43535). Based on the evidence outlined above, the variant was classified as uncertain significance. -
not provided Uncertain:2
Published functional studies demonstrate a damaging effect on the ion transport activity of pendrin(PMID: 22116359); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22116355, 22116359, 28941661, 36515421) -
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Autosomal recessive nonsyndromic hearing loss 4 Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at