rs142776952

Positions:

• chr1-119752550-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005518.4(HMGCS2):​c.1419G>A​(p.Lys473=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00497 in 1,613,912 control chromosomes in the GnomAD database, including 149 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (138 hom.)
• Consequence: HMGCS2 NM_005518.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.0002780
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.290

Genes affected

HMGCS2 (HGNC:5008): (3-hydroxy-3-methylglutaryl-CoA synthase 2) The protein encoded by this gene belongs to the HMG-CoA synthase family. It is a mitochondrial enzyme that catalyzes the first reaction of ketogenesis, a metabolic pathway that provides lipid-derived energy for various organs during times of carbohydrate deprivation, such as fasting. Mutations in this gene are associated with HMG-CoA synthase 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 1-119752550-C-T is Benign according to our data. Variant chr1-119752550-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 292330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.29 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00345 (525/152258) while in subpopulation SAS AF= 0.0386 (186/4816). AF 95% confidence interval is 0.0341. There are 11 homozygotes in gnomad4. There are 306 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HMGCS2	NM_005518.4	c.1419G>A	p.Lys473=	splice_region_variant, synonymous_variant	8/10	ENST00000369406.8	NP_005509.1
HMGCS2	NM_001166107.1	c.1293G>A	p.Lys431=	splice_region_variant, synonymous_variant	7/9		NP_001159579.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HMGCS2	ENST00000369406.8	c.1419G>A	p.Lys473=	splice_region_variant, synonymous_variant	8/10	1	NM_005518.4	ENSP00000358414	P1
HMGCS2	ENST00000544913.2	c.1293G>A	p.Lys431=	splice_region_variant, synonymous_variant	7/9	2		ENSP00000439495

Frequencies

GnomAD3 genomes AF: 0.00346 AC: 526 AN: 152140 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0388

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00322

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00797 AC: 2004 AN: 251474 Hom.: 49 AF XY: 0.0101 AC XY: 1371 AN XY: 135914

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00335

Gnomad ASJ exome AF: 0.00516

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0437

Gnomad FIN exome AF: 0.000878

Gnomad NFE exome AF: 0.00373

Gnomad OTH exome AF: 0.00750

GnomAD4 exome AF: 0.00513 AC: 7503 AN: 1461654 Hom.: 138 Cov.: 32 AF XY: 0.00646 AC XY: 4694 AN XY: 727112

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.00295

Gnomad4 ASJ exome AF: 0.00528

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0442

Gnomad4 FIN exome AF: 0.00118

Gnomad4 NFE exome AF: 0.00246

Gnomad4 OTH exome AF: 0.00573

GnomAD4 genome AF: 0.00345 AC: 525 AN: 152258 Hom.: 11 Cov.: 32 AF XY: 0.00411 AC XY: 306 AN XY: 74448

Gnomad4 AFR AF: 0.000602

Gnomad4 AMR AF: 0.00334

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0386

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00322

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00364 Hom.: 4

Bravo AF: 0.00247

Asia WGS AF: 0.0180 AC: 61 AN: 3478

EpiCase AF: 0.00534

EpiControl AF: 0.00486

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

3-hydroxy-3-methylglutaryl-CoA synthase deficiency Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 20, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 26, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 18, 2015

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	5.7
DANN	Benign	0.78

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00028
dbscSNV1_RF	Benign	0.10
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: rs142776952; hg19: chr1-120295173;