1-23802269-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000191.3(HMGCL):c.*194C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00574 in 626,058 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0051 (8 hom., cov: 33)
  • Exomes 𝑓: 0.0060 (19 hom.)
• Consequence: HMGCL NM_000191.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.209

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-23802269-G-C is Benign according to our data. Variant chr1-23802269-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 296845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00507 (773/152338) while in subpopulation NFE AF= 0.00735 (500/68024). AF 95% confidence interval is 0.00682. There are 8 homozygotes in gnomad4. There are 398 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HMGCL	NM_000191.3	c.*194C>G		3_prime_UTR_variant	9/9	ENST00000374490.8
HMGCL	NM_001166059.2	c.*194C>G		3_prime_UTR_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HMGCL	ENST00000374490.8	c.*194C>G		3_prime_UTR_variant	9/9	1	NM_000191.3	P1
HMGCL	ENST00000235958.4	c.*194C>G		3_prime_UTR_variant	5/5	5
HMGCL	ENST00000436439.6	c.*194C>G		3_prime_UTR_variant	7/7	2
HMGCL	ENST00000374487.6	n.1769C>G		non_coding_transcript_exon_variant	10/10	2

Frequencies

GnomAD3 genomes AF: 0.00508 AC: 773 AN: 152220 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00735

Gnomad OTH AF: 0.00239

GnomAD4 exome AF: 0.00596 AC: 2823 AN: 473720 Hom.: 19 Cov.: 3 AF XY: 0.00547 AC XY: 1379 AN XY: 252118

Gnomad4 AFR exome AF: 0.00189

Gnomad4 AMR exome AF: 0.00171

Gnomad4 ASJ exome AF: 0.00305

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0174

Gnomad4 NFE exome AF: 0.00731

Gnomad4 OTH exome AF: 0.00431

GnomAD4 genome AF: 0.00507 AC: 773 AN: 152338 Hom.: 8 Cov.: 33 AF XY: 0.00534 AC XY: 398 AN XY: 74496

Gnomad4 AFR AF: 0.00118

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0179

Gnomad4 NFE AF: 0.00735

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00561 Hom.: 1

Bravo AF: 0.00391

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of hydroxymethylglutaryl-CoA lyase Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 07, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	8.1
Dann	Benign	0.46
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs192071003; hg19: chr1-24128759; COSMIC: COSV52525366; COSMIC: COSV52525366;