rs719400

Variant names:

• chr1-23808231-T-C
• rs719400
• NM_000191.3:c.654A>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.23
• Publications: 25 publications found

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 Gene-Disease associations (from GenCC):

• 3-hydroxy-3-methylglutaric aciduria

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), ClinGen, G2P

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.08).
• BP6: Variant 1-23808231-T-C is Benign according to our data. Variant chr1-23808231-T-C is described in ClinVar as Benign. ClinVar VariationId is 92602.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000191.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGCL	NM_000191.3	MANE Select	c.654A>G	p.Leu218Leu	synonymous	Exon 7 of 9	NP_000182.2	P35914-1
	HMGCL	NM_001166059.2		c.441A>G	p.Leu147Leu	synonymous	Exon 5 of 7	NP_001159531.1	P35914-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGCL	ENST00000374490.8	TSL:1 MANE Select	c.654A>G	p.Leu218Leu	synonymous	Exon 7 of 9	ENSP00000363614.3	P35914-1
	HMGCL	ENST00000509389.5	TSL:1	n.361-16A>G		intron	N/A
	HMGCL	ENST00000892104.1		c.654A>G	p.Leu218Leu	synonymous	Exon 7 of 10	ENSP00000562163.1

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

GnomAD2 exomes AF: 0.902 AC: 226778 AN: 251422 AF XY: 0.900

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 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

African (AFR) AF: 0.968 AC: 32401 AN: 33476

American (AMR) AF: 0.893 AC: 39916 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.871 AC: 22760 AN: 26136

East Asian (EAS) AF: 0.824 AC: 32698 AN: 39700

South Asian (SAS) AF: 0.880 AC: 75919 AN: 86252

European-Finnish (FIN) AF: 0.958 AC: 51157 AN: 53388

Middle Eastern (MID) AF: 0.940 AC: 5421 AN: 5766

European-Non Finnish (NFE) AF: 0.915 AC: 1017266 AN: 1111878

Other (OTH) AF: 0.908 AC: 54818 AN: 60390

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

African (AFR) AF: 0.966 AC: 40100 AN: 41522

American (AMR) AF: 0.888 AC: 13564 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.868 AC: 3013 AN: 3470

East Asian (EAS) AF: 0.791 AC: 4074 AN: 5150

South Asian (SAS) AF: 0.867 AC: 4186 AN: 4828

European-Finnish (FIN) AF: 0.965 AC: 10232 AN: 10608

Middle Eastern (MID) AF: 0.932 AC: 274 AN: 294

European-Non Finnish (NFE) AF: 0.915 AC: 62183 AN: 67994

Other (OTH) AF: 0.917 AC: 1937 AN: 2112

Alfa AF: 0.912 Hom.: 120854

Bravo AF: 0.920

Asia WGS AF: 0.833 AC: 2898 AN: 3478

EpiCase AF: 0.906

EpiControl AF: 0.907

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	Deficiency of hydroxymethylglutaryl-CoA lyase (4)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	8.6
DANN	Benign	0.71
PhyloP100		1.2
Mutation Taster		=92/8	polymorphism (auto)

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

Other links and lift over

dbSNP: rs719400; hg19: chr1-24134721; COSMIC: COSV108035619; COSMIC: COSV108035619;