rs111033312
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_000441.2(SLC26A4):c.1614+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000277 in 1,591,200 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 22 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC26A4 | NM_000441.2 | c.1614+1G>A | splice_donor_variant | ENST00000644269.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC26A4 | ENST00000644269.2 | c.1614+1G>A | splice_donor_variant | NM_000441.2 | P1 | ||||
SLC26A4 | ENST00000644846.1 | c.325+1G>A | splice_donor_variant, NMD_transcript_variant | ||||||
SLC26A4 | ENST00000477350.5 | n.461+1G>A | splice_donor_variant, non_coding_transcript_variant | 4 | |||||
SLC26A4 | ENST00000480841.5 | n.463+1G>A | splice_donor_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 152052Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251028Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135668
GnomAD4 exome AF: 0.0000292 AC: 42AN: 1439148Hom.: 0 Cov.: 26 AF XY: 0.0000223 AC XY: 16AN XY: 717484
GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 152052Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74272
ClinVar
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
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 26, 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:3
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 03, 2021 | NM_000441.1(SLC26A4):c.1614+1G>A is a canonical splice variant classified as pathogenic in the context of Pendred syndrome. c.1614+1G>A has been observed in cases with relevant disease (PMID: 15355436). Functional assessments of this variant are not available in the literature. c.1614+1G>A has been observed in population frequency databases (gnomAD: NFE 0.004%). In summary, NM_000441.1(SLC26A4):c.1614+1G>A is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 01, 2023 | This sequence change affects a donor splice site in intron 14 of the SLC26A4 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SLC26A4 are known to be pathogenic (PMID: 16283880, 25394566, 26252218, 26445815). This variant is present in population databases (rs111033312, gnomAD 0.004%). Disruption of this splice site has been observed in individuals with nonsyndromic enlarged vestibular aqueduct and hearing loss (PMID: 11919333, 15355436, 20128824, 20597900, 24105851). ClinVar contains an entry for this variant (Variation ID: 43516). 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 | Dec 23, 2021 | Canonical splice site variant 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: 25525159, 21704276, 30368370, 30651814, 30268946, 31589614, 18285825, 32645618, 15355436, 11919333, 31541171, 24105851, 33597575, 20128824, 20597900) - |
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 09, 2015 | The c.1614+1G>A variant in SLC26A4 has been reported in 13 individuals with hear ing loss or Pendred syndrome, and 8 of them were compound heterozygous (Fugazzol a 2002, Blons 2004, Pera 2008, Pourova 2010, LMM unpublished data). This variant has also been identified in 3/66512 European chromosomes by the Exome Aggregati on Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs111033312). Althoug h this variant has been seen in the general population, its frequency is low eno ugh to be consistent with a recessive carrier frequency. This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. In summary, this variant meets our criteria to be classified as pathogenic. - |
Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 16, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at