chr1-23814186-T-C
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5
The NM_000191.3(HMGCL):c.497+4A>G 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 0.00000616 in 1,461,262 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000191.3 splice_donor_region, 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 |
---|---|---|---|---|---|---|---|
HMGCL | NM_000191.3 | c.497+4A>G | splice_donor_region_variant, intron_variant | ENST00000374490.8 | |||
HMGCL | NM_001166059.2 | c.348+2489A>G | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HMGCL | ENST00000374490.8 | c.497+4A>G | splice_donor_region_variant, intron_variant | 1 | NM_000191.3 | P1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251470Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135908
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461262Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6AN XY: 726968
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Deficiency of hydroxymethylglutaryl-CoA lyase Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Feb 14, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 20, 2024 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 05, 2015 | An individual with symptoms associated with HMG-CoA lyase deficiency was heterozygous for this variant and a nonsense variant; however, parental testing was not done to confirm the variants were in trans (Menao et al., 2009). Functional analysis found that the c.497+4 A>G variant results in alternative splicing with 2 transcripts, one bearing a five-exon deletion and the other with deletion of exons 5 and 6 (Menao et al., 2009). Additionally, this nucleotide substitution occurs at a position that is conserved across species and several in-silico splice prediction models predict that c.497+4 A>G creates a cryptic donor site in intron 5. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at