rs56218308
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The ENST00000374490.8(HMGCL):āc.393A>Gā(p.Ser131=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000483 in 1,614,072 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā ā ).
Frequency
Genomes: š 0.0027 ( 3 hom., cov: 31)
Exomes š: 0.00025 ( 1 hom. )
Consequence
HMGCL
ENST00000374490.8 synonymous
ENST00000374490.8 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -3.67
Genes affected
HMGCL (HGNC:5005): (3-hydroxy-3-methylglutaryl-CoA lyase) The protein encoded by this gene belongs to the HMG-CoA lyase family. It is a mitochondrial enzyme that catalyzes the final step of leucine degradation and plays a key role in ketone body formation. Mutations in this gene are associated with HMG-CoA lyase deficiency. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -21 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.89).
BP6
Variant 1-23814294-T-C is Benign according to our data. Variant chr1-23814294-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 382367.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-3.67 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0027 (411/152326) while in subpopulation AFR AF= 0.00914 (380/41582). AF 95% confidence interval is 0.00838. There are 3 homozygotes in gnomad4. There are 204 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 3 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HMGCL | NM_000191.3 | c.393A>G | p.Ser131= | synonymous_variant | 5/9 | ENST00000374490.8 | NP_000182.2 | |
HMGCL | NM_001166059.2 | c.348+2381A>G | intron_variant | NP_001159531.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HMGCL | ENST00000374490.8 | c.393A>G | p.Ser131= | synonymous_variant | 5/9 | 1 | NM_000191.3 | ENSP00000363614 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00269 AC: 410AN: 152208Hom.: 3 Cov.: 31
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GnomAD3 exomes AF: 0.000648 AC: 163AN: 251468Hom.: 1 AF XY: 0.000449 AC XY: 61AN XY: 135910
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GnomAD4 exome AF: 0.000252 AC: 368AN: 1461746Hom.: 1 Cov.: 31 AF XY: 0.000224 AC XY: 163AN XY: 727184
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GnomAD4 genome AF: 0.00270 AC: 411AN: 152326Hom.: 3 Cov.: 31 AF XY: 0.00274 AC XY: 204AN XY: 74488
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:3
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | HMGCL: BP4, BP7, BS2 - |
Benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 17, 2020 | - - |
Deficiency of hydroxymethylglutaryl-CoA lyase Benign:2
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency Benign:1
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Dec 04, 2019 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at