rs192366176
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_000441.2(SLC26A4):c.1707+5G>A variant causes a splice donor 5th base, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000494 in 1,417,066 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_000441.2 splice_donor_5th_base, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SLC26A4 | NM_000441.2 | c.1707+5G>A | splice_donor_5th_base_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.1707+5G>A | splice_donor_5th_base_variant, intron_variant | NM_000441.2 | ENSP00000494017 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152178Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000802 AC: 2AN: 249476Hom.: 0 AF XY: 0.00000741 AC XY: 1AN XY: 134942
GnomAD4 exome AF: 0.00000316 AC: 4AN: 1264770Hom.: 0 Cov.: 19 AF XY: 0.00000313 AC XY: 2AN XY: 639850
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152296Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74474
ClinVar
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:3Other:1
Affects, no assertion criteria provided | clinical testing;in vitro | National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center | Aug 20, 2019 | in vitro experiment - |
Pathogenic, criteria provided, single submitter | clinical testing | Division of Hearing and Balance Research, National Hospital Organization Tokyo Medical Center | Jul 01, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 24, 2024 | - - |
Pathogenic, no assertion criteria provided | case-control | Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital | Feb 26, 2019 | - - |
Pendred syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Sep 07, 2017 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 05, 2021 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 18, 2023 | This sequence change falls in intron 15 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 present in population databases (rs192366176, gnomAD 0.006%). This variant has been observed in individuals with Pendred syndrome or sensorineural hearing loss and enlarged vestibular aqueduct (PMID: 21961810, 23705809, 26763877). This variant is also known as IVS15+5G>A. ClinVar contains an entry for this variant (Variation ID: 446457). 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. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 08, 2018 | The c.1707+5 G>A splice site variant in the SLC26A4 gene has been previously reported in both the homozygous and compound heterozygous state in association with SLC26A4-related disorders (Ganaha et al., 2013; Hao et al., 2018; Yang et al., 2005). The variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). This pathogenic variant destroys the natural splice donor site in intron 15, and is expected to cause abnormal gene splicing. In summary, we consider this to be a pathogenic variant. - |
Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Juno Genomics, Hangzhou Juno Genomics, Inc | - | PM3_VeryStrong+PP4+PS3_Moderate - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at