rs201180712
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_139319.3(SLC17A8):c.1396C>A(p.Leu466Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000688 in 1,614,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_139319.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC17A8 | NM_139319.3 | c.1396C>A | p.Leu466Ile | missense_variant | 11/12 | ENST00000323346.10 | |
SLC17A8 | NM_001145288.2 | c.1246C>A | p.Leu416Ile | missense_variant | 10/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC17A8 | ENST00000323346.10 | c.1396C>A | p.Leu466Ile | missense_variant | 11/12 | 1 | NM_139319.3 | P1 | |
SLC17A8 | ENST00000392989.3 | c.1246C>A | p.Leu416Ile | missense_variant | 10/11 | 1 | |||
SLC17A8 | ENST00000552697.1 | n.289C>A | non_coding_transcript_exon_variant | 3/4 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000657 AC: 10AN: 152130Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000143 AC: 36AN: 251322Hom.: 0 AF XY: 0.000140 AC XY: 19AN XY: 135824
GnomAD4 exome AF: 0.0000691 AC: 101AN: 1461876Hom.: 0 Cov.: 32 AF XY: 0.0000660 AC XY: 48AN XY: 727238
GnomAD4 genome ? AF: 0.0000657 AC: 10AN: 152130Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74326
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 01, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 18, 2022 | In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 19, 2014 | Variant classified as Uncertain Significance - Favor Benign. The Leu466Ile varia nt in SLC17A8 has not been reported in individuals with hearing loss, but has be en identified in 1/1323 of European Chromosomes by the ClinSeq project (http://w ww.genome.gov/20519355; dbSNP rs201180712). The leucine (Leu) at position 466 is conserved in mammals, but not in birds or evolutionarily distant species, with scarlet macaw and softshell turtle having an isoleucine (Ile) at this position, supporting that this change may be tolerated. Additional computational predicti on tools also suggest this variant may not impact the protein, though this infor mation is not predictive enough to rule out pathogenicity. In summary, the clini cal significance of this variant cannot be determined with certainty; however, t he conservation and computational data suggest that it is more likely to be beni gn. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 21, 2022 | The c.1396C>A (p.L466I) alteration is located in exon 11 (coding exon 11) of the SLC17A8 gene. This alteration results from a C to A substitution at nucleotide position 1396, causing the leucine (L) at amino acid position 466 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Autosomal dominant nonsyndromic hearing loss 25 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at