12-100380957-G-C
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Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_139319.3(SLC17A8):c.354+4G>C variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,674 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: not found (cov: 31)
Exomes 𝑓: 0.000010 ( 0 hom. )
Consequence
SLC17A8
NM_139319.3 splice_donor_region, intron
NM_139319.3 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.00002740
2
Clinical Significance
Conservation
PhyloP100: 0.494
Genes affected
SLC17A8 (HGNC:20151): (solute carrier family 17 member 8) This gene encodes a vesicular glutamate transporter. The encoded protein transports the neurotransmitter glutamate into synaptic vesicles before it is released into the synaptic cleft. Mutations in this gene are the cause of autosomal-dominant nonsyndromic type 25 deafness. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2010]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -8 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.81).
BS2
High AC in GnomAdExome4 at 15 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC17A8 | NM_139319.3 | c.354+4G>C | splice_donor_region_variant, intron_variant | ENST00000323346.10 | |||
SLC17A8 | NM_001145288.2 | c.354+4G>C | splice_donor_region_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC17A8 | ENST00000323346.10 | c.354+4G>C | splice_donor_region_variant, intron_variant | 1 | NM_139319.3 | P1 | |||
SLC17A8 | ENST00000392989.3 | c.354+4G>C | splice_donor_region_variant, intron_variant | 1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 genomes
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31
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251260Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135800
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GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461674Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13AN XY: 727150
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GnomAD4 genome Cov.: 31
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31
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 19, 2013 | Variant classified as Uncertain Significance - Favor Benign. The 354+4G>C varian t in SLC17A8 has not been previously reported in individuals with hearing loss o r in large population studies. This variant is located in the 5' splice region but not in the invariant (+1/2) positions of the splice site consensus sequence and computational tools do not suggest and impact to splicing. However, this inf ormation is not predictive enough to rule out pathogenicity. In summary, the cli nical significance of this variant cannot be determined with certainty; however based upon the computational data, we would lean towards a more likely benign ro le. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
Name
Calibrated prediction
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at