chr1-23802483-G-A

Variant names:

• chr1-23802483-G-A
• rs1553131326
• NM_000191.3:c.958C>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_000191.3(HMGCL):​c.958C>T​(p.Gln320*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. Q320Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HMGCL NM_000191.3 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.98

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.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0204 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• 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.958C>T	p.Gln320*	stop_gained	Exon 9 of 9	ENST00000374490.8	NP_000182.2
HMGCL	NM_001166059.2	c.745C>T	p.Gln249*	stop_gained	Exon 7 of 7		NP_001159531.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMGCL	ENST00000374490.8	c.958C>T	p.Gln320*	stop_gained	Exon 9 of 9	1	NM_000191.3	ENSP00000363614.3
HMGCL	ENST00000436439.6	c.745C>T	p.Gln249*	stop_gained	Exon 7 of 7	2		ENSP00000389281.2
HMGCL	ENST00000235958.4	c.526C>T	p.Gln176*	stop_gained	Exon 5 of 5	5		ENSP00000235958.4
HMGCL	ENST00000374487.6	n.1555C>T		non_coding_transcript_exon_variant	Exon 10 of 10	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Deficiency of hydroxymethylglutaryl-CoA lyase Uncertain:1

Jun 09, 2017

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
Vest4		0.36
GERP RS		4.1

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: rs1553131326; hg19: chr1-24128973;