rs1286992834

Variant names:

• chr1-119755536-A-C
• rs1286992834
• NM_005518.4:c.1078T>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_005518.4(HMGCS2):​c.1078T>G​(p.Ser360Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S360S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HMGCS2 NM_005518.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.26
• Publications: 0 publications found

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]

HMGCS2 Gene-Disease associations (from GenCC):

• 3-hydroxy-3-methylglutaryl-CoA synthase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet, ClinGen, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 13 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: -0.19124 (below the threshold of 3.09). Trascript score misZ: 0.52753 (below the threshold of 3.09). GenCC associations: The gene is linked to 3-hydroxy-3-methylglutaryl-CoA synthase deficiency.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.807

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005518.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGCS2	NM_005518.4	MANE Select	c.1078T>G	p.Ser360Ala	missense	Exon 6 of 10	NP_005509.1
	HMGCS2	NM_001166107.1		c.952T>G	p.Ser318Ala	missense	Exon 5 of 9	NP_001159579.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGCS2	ENST00000369406.8	TSL:1 MANE Select	c.1078T>G	p.Ser360Ala	missense	Exon 6 of 10	ENSP00000358414.3
	HMGCS2	ENST00000544913.2	TSL:2	c.952T>G	p.Ser318Ala	missense	Exon 5 of 9	ENSP00000439495.2
	HMGCS2	ENST00000472375.5	TSL:5	n.525T>G		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251486 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461854 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727224

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111974

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

3-hydroxy-3-methylglutaryl-CoA synthase deficiency Uncertain:1

Mar 22, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with HMGCS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 470720). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 360 of the HMGCS2 protein (p.Ser360Ala).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.73	D
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.023	T
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	1.0	L
PhyloP100		6.3
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.55
Sift	Benign	0.49	T
Sift4G	Benign	0.44	T
Polyphen		0.66	P
Vest4		0.69
MutPred		0.63		Loss of phosphorylation at S360 (P = 0.0294)
MVP		0.83
MPC		0.47
ClinPred		0.88	D
GERP RS		5.3
Varity_R		0.36
gMVP		0.35
Mutation Taster		=53/47	polymorphism

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

Other links and lift over

dbSNP: rs1286992834; hg19: chr1-120298159;