1-23802359-C-T

Position:

• chr1-23802359-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_000191.3(HMGCL):​c.*104G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00198 in 821,374 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (5 hom.)
• Consequence: HMGCL NM_000191.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.470

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00178 (270/151276) while in subpopulation NFE AF= 0.00254 (172/67678). AF 95% confidence interval is 0.00223. There are 0 homozygotes in gnomad4. There are 124 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HMGCL	NM_000191.3	c.*104G>A		3_prime_UTR_variant	9/9	ENST00000374490.8
HMGCL	NM_001166059.2	c.*104G>A		3_prime_UTR_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HMGCL	ENST00000374490.8	c.*104G>A		3_prime_UTR_variant	9/9	1	NM_000191.3	P1
HMGCL	ENST00000235958.4	c.*104G>A		3_prime_UTR_variant	5/5	5
HMGCL	ENST00000436439.6	c.*104G>A		3_prime_UTR_variant	7/7	2
HMGCL	ENST00000374487.6	n.1679G>A		non_coding_transcript_exon_variant	10/10	2

Frequencies

GnomAD3 genomes AF: 0.00179 AC: 271 AN: 151156 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000755

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00224

Gnomad ASJ AF: 0.00550

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000840

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00962

Gnomad NFE AF: 0.00254

Gnomad OTH AF: 0.00384

GnomAD4 exome AF: 0.00203 AC: 1358 AN: 670098 Hom.: 5 Cov.: 8 AF XY: 0.00198 AC XY: 719 AN XY: 362242

Gnomad4 AFR exome AF: 0.000758

Gnomad4 AMR exome AF: 0.00293

Gnomad4 ASJ exome AF: 0.00453

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000633

Gnomad4 FIN exome AF: 0.000149

Gnomad4 NFE exome AF: 0.00247

Gnomad4 OTH exome AF: 0.00237

GnomAD4 genome AF: 0.00178 AC: 270 AN: 151276 Hom.: 0 Cov.: 33 AF XY: 0.00168 AC XY: 124 AN XY: 73934

Gnomad4 AFR AF: 0.000753

Gnomad4 AMR AF: 0.00223

Gnomad4 ASJ AF: 0.00550

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000841

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00254

Gnomad4 OTH AF: 0.00380

Alfa AF: 0.00222 Hom.: 0

Bravo AF: 0.00191

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of hydroxymethylglutaryl-CoA lyase Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	5.1
DANN	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs552915017; hg19: chr1-24128849;