rs719400

chr1-23808231-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000191.3(HMGCL):c.654A>G(p.Leu218=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.913 in 1,613,874 control chromosomes in the GnomAD database, including 672,772 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L218L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.92 (64921 hom., cov: 31)
  • Exomes 𝑓: 0.91 (607851 hom.)
• Consequence: HMGCL NM_000191.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.23

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 1-23808231-T-C is Benign according to our data. Variant chr1-23808231-T-C is described in ClinVar as [Benign]. Clinvar id is 92602.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-23808231-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.23 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.958 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HMGCL	NM_000191.3	c.654A>G	p.Leu218=	synonymous_variant	7/9	ENST00000374490.8
HMGCL	NM_001166059.2	c.441A>G	p.Leu147=	synonymous_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HMGCL	ENST00000374490.8	c.654A>G	p.Leu218=	synonymous_variant	7/9	1	NM_000191.3	P1

Frequencies

GnomAD3 genomes AF: 0.923 AC: 140340 AN: 152052 Hom.: 64879 Cov.: 31

Gnomad AFR AF: 0.966

Gnomad AMI AF: 0.966

Gnomad AMR AF: 0.887

Gnomad ASJ AF: 0.868

Gnomad EAS AF: 0.791

Gnomad SAS AF: 0.867

Gnomad FIN AF: 0.965

Gnomad MID AF: 0.930

Gnomad NFE AF: 0.915

Gnomad OTH AF: 0.924

GnomAD3 exomes AF: 0.902 AC: 226778 AN: 251422 Hom.: 102541 AF XY: 0.900 AC XY: 122353 AN XY: 135884

Gnomad AFR exome AF: 0.968

Gnomad AMR exome AF: 0.894

Gnomad ASJ exome AF: 0.869

Gnomad EAS exome AF: 0.788

Gnomad SAS exome AF: 0.874

Gnomad FIN exome AF: 0.960

Gnomad NFE exome AF: 0.913

Gnomad OTH exome AF: 0.910

GnomAD4 exome AF: 0.912 AC: 1332356 AN: 1461704 Hom.: 607851 Cov.: 47 AF XY: 0.910 AC XY: 661880 AN XY: 727162

Gnomad4 AFR exome AF: 0.968

Gnomad4 AMR exome AF: 0.893

Gnomad4 ASJ exome AF: 0.871

Gnomad4 EAS exome AF: 0.824

Gnomad4 SAS exome AF: 0.880

Gnomad4 FIN exome AF: 0.958

Gnomad4 NFE exome AF: 0.915

Gnomad4 OTH exome AF: 0.908

GnomAD4 genome AF: 0.923 AC: 140444 AN: 152170 Hom.: 64921 Cov.: 31 AF XY: 0.923 AC XY: 68686 AN XY: 74392

Gnomad4 AFR AF: 0.966

Gnomad4 AMR AF: 0.888

Gnomad4 ASJ AF: 0.868

Gnomad4 EAS AF: 0.791

Gnomad4 SAS AF: 0.867

Gnomad4 FIN AF: 0.965

Gnomad4 NFE AF: 0.915

Gnomad4 OTH AF: 0.917

Alfa AF: 0.912 Hom.: 83065

Bravo AF: 0.920

Asia WGS AF: 0.833 AC: 2898 AN: 3478

EpiCase AF: 0.906

EpiControl AF: 0.907

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 10, 2014	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 29, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Deficiency of hydroxymethylglutaryl-CoA lyase Benign:4

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
Cadd	Benign	8.6
Dann	Benign	0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs719400; hg19: chr1-24134721;