NM_000191.3:c.920G>C

Variant names:

• chr1-23802521-C-G
• NM_000191.3:c.920G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000191.3(HMGCL):​c.920G>C​(p.Cys307Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,816 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C307Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HMGCL NM_000191.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.07

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a chain Hydroxymethylglutaryl-CoA lyase, mitochondrial (size 297) in uniprot entity HMGCL_HUMAN there are 44 pathogenic changes around while only 5 benign (90%) in NM_000191.3
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMGCL	NM_000191.3	c.920G>C	p.Cys307Ser	missense_variant	Exon 9 of 9	ENST00000374490.8	NP_000182.2
HMGCL	NM_001166059.2	c.707G>C	p.Cys236Ser	missense_variant	Exon 7 of 7		NP_001159531.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMGCL	ENST00000374490.8	c.920G>C	p.Cys307Ser	missense_variant	Exon 9 of 9	1	NM_000191.3	ENSP00000363614.3
HMGCL	ENST00000436439.6	c.707G>C	p.Cys236Ser	missense_variant	Exon 7 of 7	2		ENSP00000389281.2
HMGCL	ENST00000235958.4	c.488G>C	p.Cys163Ser	missense_variant	Exon 5 of 5	5		ENSP00000235958.4
HMGCL	ENST00000374487.6	n.1517G>C		non_coding_transcript_exon_variant	Exon 10 of 10	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461816 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727220

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	21
DANN	Benign	0.88
DEOGEN2	Pathogenic	0.91	D;.
Eigen	Benign	0.072
Eigen_PC	Benign	0.17
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.071	D
MetaRNN	Uncertain	0.68	D;D
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.29	N;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.3	D;D
REVEL	Uncertain	0.56
Sift	Benign	0.97	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.010	B;.
Vest4		0.56
MutPred		0.65		Gain of disorder (P = 0.0028);.;
MVP		0.90
MPC		0.18
ClinPred		0.75	D
GERP RS		3.9
Varity_R		0.61
gMVP		0.83

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-24129011;