rs759360026
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3
The NM_000441.2(SLC26A4):c.1678G>A(p.Asp560Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000246 in 1,587,524 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000441.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 152068Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 250728Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135504
GnomAD4 exome AF: 0.0000258 AC: 37AN: 1435456Hom.: 0 Cov.: 26 AF XY: 0.0000265 AC XY: 19AN XY: 715926
GnomAD4 genome AF: 0.0000132 AC: 2AN: 152068Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74288
ClinVar
Submissions by phenotype
not specified Uncertain:2
The p.Asp560Asn variant in SLC26A4 has been reported in 1 Chinese individual wit h nonsyndromic hearing loss (Yuan 2012). However, information was not provided r egarding if this individual had a second SLC26A4 variant or temporal bone abnorm alities consistent with SLC26A4-related hearing loss. This variant was also iden tified in 3/120123 chromosomes by the Exome Aggregation Consortium (ExAC, http:/ /exac.broadinstitute.org). Although this variant has been seen in the general po pulation, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that the Asp560Asn variant may impact the protein, though this information is not pr edictive enough to determine pathogenicity. In summary, the clinical significanc e of the Asp560Asn variant is uncertain. -
Variant summary: SLC26A4 c.1678G>A (p.Asp560Asn) results in a conservative amino acid change located in the STAS domain (IPR002645) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 250728 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1678G>A has been reported in the literature as a causative variant in compound heterozygosity with another causative variant in at-least one index case affected with hearing loss from a family history of three affected individuals. However, the genotyping of the additional individuals is not specified. It has also been reported as a non-informative genotype (second allele not specified) in another family. These data do not allow any conclusion about variant significance (example, Yuan_2012, Lebeko_2016 cited in Wonkam_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23838540, 27246798, 33528103, 23185506). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=3; LP, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Pendred syndrome Uncertain:2
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Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:1
This variant was found in compound heterozygosity with an SLC26A4 nonsense variant that is known to be pathogenic, in a patient with bilateral sensorineural hearing loss of onset <18 years, in a study of pediatric hearing loss conducted by the King Laboratory (Carlson RJ et al. JAMA-OtoHNS 2023). This patient has a 1st cousin with hearing loss, but has no other family history of childhood-onset hearing loss. This variant is a missense at a highly conserved site and is predicted to be damaging by multiple in-silico tools. As of January 2023, this variant has been reported previously in an individual with hearing loss and is currently classified as a variant of unknown significance on ClinVar, and it is found in 6 heterozygous individuals on gnomAD. Based on compound heterozygosity with a loss-of-function variant, consistently predicted functional effect, and goodness of fit of genotype to phenotype, we conclude that this variant is likely pathogenic. -
Pendred syndrome;C3538946: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