NM_000191.3:c.654A>G

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000191.3(HMGCL):c.654A>G(p.Leu218Leu) 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 1.23

Variant links:

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]

HMGCL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
HMGCL	NM_000191.3 link	c.654A>G	p.Leu218Leu	synonymous_variant	Exon 7 of 9	ENST00000374490.8	NP_000182.2	P35914-1
HMGCL	NM_001166059.2 link	c.441A>G	p.Leu147Leu	synonymous_variant	Exon 5 of 7		NP_001159531.1	P35914-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMGCL	ENST00000374490.8 link	c.654A>G	p.Leu218Leu	synonymous_variant	Exon 7 of 9	1	NM_000191.3	ENSP00000363614.3		P35914-1

Frequencies

GnomAD3 genomes

AF:

0.923

AC:

140340

AN:

152052

Hom.:

64879

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.910

AC XY:

661880

AN XY:

727162

show subpopulations

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.:

AF XY:

0.923

AC XY:

68686

AN XY:

74392

show subpopulations

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:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 29, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 10, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Deficiency of hydroxymethylglutaryl-CoA lyase

Benign:4

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over