rs368280107
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_000441.2(SLC26A4):c.415+4A>G variant causes a splice donor region, intron change. The variant allele was found at a frequency of 0.00000589 in 1,527,534 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000015 ( 0 hom. )
Consequence
SLC26A4
NM_000441.2 splice_donor_region, intron
NM_000441.2 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.9996
2
Clinical Significance
Conservation
PhyloP100: 4.45
Genes affected
SLC26A4 (HGNC:8818): (solute carrier family 26 member 4) Mutations in this gene are associated with Pendred syndrome, the most common form of syndromic deafness, an autosomal-recessive disease. It is highly homologous to the SLC26A3 gene; they have similar genomic structures and this gene is located 3' of the SLC26A3 gene. The encoded protein has homology to sulfate transporters. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC26A4 | NM_000441.2 | c.415+4A>G | splice_donor_region_variant, intron_variant | ENST00000644269.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC26A4 | ENST00000644269.2 | c.415+4A>G | splice_donor_region_variant, intron_variant | NM_000441.2 | P1 | ||||
SLC26A4 | ENST00000440056.1 | downstream_gene_variant | 4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152034Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.00000797 AC: 2AN: 251052Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135710
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GnomAD4 exome AF: 0.00000145 AC: 2AN: 1375500Hom.: 0 Cov.: 22 AF XY: 0.00000145 AC XY: 1AN XY: 689550
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GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152034Hom.: 0 Cov.: 31 AF XY: 0.0000539 AC XY: 4AN XY: 74274
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 13, 2016 | Variant classified as Uncertain Significance - Favor Pathogenic. The c.415+4A>G variant in SLC26A4 has been reported in the compound heterozygous state with a s econd SLC26A4 variant in 1 Korean individual with hearing loss and enlarged vest ibular aqueducts (Park 2005). This variant has been identified in 2/10202 Afric an chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinsti tute.org; dbSNP rs368280107); however, its frequency is not high enough to rule out a pathogenic role. This variant is located in the 5' splice region. Computat ional tools suggest an impact to splicing. However, this information is not pred ictive enough to determine pathogenicity. In summary, while the clinical signifi cance of this variant is uncertain, available data suggest that this variant is more likely to be pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 14, 2021 | Variant summary: SLC26A4 c.415+4A>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: two predict the variant abolishes a 5 prime splicing donor site; one predict the variant weakens a 5 prime donor site. However, one experimental study showed that this variant did not affect normal splicing (Lee_2019). The variant allele was found at a frequency of 8e-06 in 251052 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.415+4A>G has been reported in the literature in individuals affected with hearing loss (Park_2004). This report does not provide unequivocal conclusions about association of the variant with Pendred Syndrome. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Pendred syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Mar 08, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Autosomal recessive nonsyndromic hearing loss 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 17, 2022 | In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 31033086, 15679828) - |
Computational scores
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Name
Calibrated prediction
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Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Calibrated prediction
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -4
Find out detailed SpliceAI scores and Pangolin per-transcript scores at