NM_000191.3:c.933C>G

Variant names:

• chr1-23802508-G-C
• rs1194563406
• NM_000191.3:c.933C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_000191.3(HMGCL):​c.933C>G​(p.Asn311Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,790 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N311D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: HMGCL NM_000191.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.91
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 0.46042 (below the threshold of 3.09). Trascript score misZ: 0.32928 (below the threshold of 3.09). GenCC associations: The gene is linked to 3-hydroxy-3-methylglutaric aciduria.

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.933C>G	p.Asn311Lys	missense	Exon 9 of 9	NP_000182.2	P35914-1
	HMGCL	NM_001166059.2		c.720C>G	p.Asn240Lys	missense	Exon 7 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.933C>G	p.Asn311Lys	missense	Exon 9 of 9	ENSP00000363614.3	P35914-1
	HMGCL	ENST00000892104.1		c.1065C>G	p.Asn355Lys	missense	Exon 10 of 10	ENSP00000562163.1
	HMGCL	ENST00000892105.1		c.1020C>G	p.Asn340Lys	missense	Exon 9 of 9	ENSP00000562164.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461790 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727200

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111926

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Deficiency of hydroxymethylglutaryl-CoA lyase (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.79	D
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.038	D
MetaRNN	Uncertain	0.43	T
MetaSVM	Benign	-0.64	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		3.9
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.52
Sift	Benign	0.069	T
Sift4G	Uncertain	0.038	D
Polyphen		0.071	B
Vest4		0.44
MutPred		0.55		Loss of helix (P = 0.0123)
MVP		0.96
MPC		0.22
ClinPred		0.98	D
GERP RS		3.9
Varity_R		0.51
gMVP		0.73
Mutation Taster		=49/51	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1194563406; hg19: chr1-24128998;