NM_004168.4:c.1794+3G>C
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_004168.4(SDHA):c.1794+3G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,613,818 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 predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_004168.4 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SDHA | NM_004168.4 | c.1794+3G>C | splice_region_variant, intron_variant | Intron 13 of 14 | ENST00000264932.11 | NP_004159.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SDHA | ENST00000264932.11 | c.1794+3G>C | splice_region_variant, intron_variant | Intron 13 of 14 | 1 | NM_004168.4 | ENSP00000264932.6 | |||
ENSG00000286001 | ENST00000651543.1 | n.*527+3G>C | splice_region_variant, intron_variant | Intron 12 of 23 | ENSP00000499215.1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152224Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000399 AC: 10AN: 250688Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135542
GnomAD4 exome AF: 0.0000219 AC: 32AN: 1461594Hom.: 0 Cov.: 32 AF XY: 0.0000193 AC XY: 14AN XY: 727112
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152224Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74362
ClinVar
Submissions by phenotype
not provided Uncertain:3
In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Has not been previously published as pathogenic or benign to our knowledge -
The frequency of this variant in the general population, 0.00025 (9/35396 chromosomes in Latino/Admixed American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper SDHA mRNA splicing . Based on the available information, we are unable to determine the clinical significance of this variant. -
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SDHA-related disorder Uncertain:1
The SDHA c.1794+3G>C variant is predicted to interfere with splicing. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.025% of alleles in individuals of Latino descent in gnomAD and has conflicting interpretations of likely benign and uncertain significance in ClinVar ranging from likely benign to uncertain significance (https://preview.ncbi.nlm.nih.gov/clinvar/variation/229686/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Paragangliomas 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1 Benign:1
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Hereditary cancer-predisposing syndrome Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at