chr7-107660860-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5
The NM_000441.2(SLC26A4):c.-4+5G>A variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000657 in 152,188 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000441.2 splice_donor_5th_base, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC26A4 | NM_000441.2 | c.-4+5G>A | splice_donor_5th_base_variant, intron_variant | ENST00000644269.2 | |||
SLC26A4-AS1 | NR_028137.1 | n.198-654C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC26A4 | ENST00000644269.2 | c.-4+5G>A | splice_donor_5th_base_variant, intron_variant | NM_000441.2 | P1 | ||||
SLC26A4-AS1 | ENST00000668981.1 | n.257+742C>T | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes AF: 0.0000657 AC: 10AN: 152188Hom.: 0 Cov.: 32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 114Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0AN XY: 86
GnomAD4 genome AF: 0.0000657 AC: 10AN: 152188Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74346
ClinVar
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | King Laboratory, University of Washington | Feb 28, 2023 | This variant was found in compound heterozygosity with an SLC26A4 splicing 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's family has no history of childhood-onset hearing loss. This variant is a single base pair substitution within the 5’ UTR that is predicted to interfere with normal splicing. As of January 2023, this variant has been reported to ClinVar as likely pathogenic and is found in 2 heterozygotes 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. - |
Rare genetic deafness Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 17, 2014 | The -4+5G>A variant in SLC26A4 has been identified in one individual with hearin g loss and EVA by our laboratory (LMM unpublished data) likely in trans with an other pathogenic variant SLC26A4 variant. In addition, this variant has not bee n identified in large population studies and is located in the 5' splice region. Computational tools suggest a possible impact to splicing; though this informat ion is not predictive enough to determine pathogenicity. In summary, this varia nt is likely pathogenic. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 24, 2023 | - - |
SLC26A4-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 17, 2024 | The SLC26A4 c.-4+5G>A variant is located in the 5' untranslated region. This variant is located in the 5' untranslated region and is predicted to possibly impact splicing (Alamut Visual v2.11). To our knowledge, this variant has not been reported in the literature but has been reported in ClinVar as being likely in trans to a second pathogenic variant in a patient with hearing loss and enlarged vestibular aqueduct (https://www.ncbi.nlm.nih.gov/clinvar/variation/165245/). This variant is reported in 0.24% of alleles in individuals of Latino descent, and in 2 of ~31,000 total alleles in the gnomAD database. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at