1-119750807-C-A

Variant names:

• chr1-119750807-C-A
• rs76773981
• NM_005518.4:c.1522G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 5P and 2B. PM1 PM2 PP2 BP4_Moderate

The NM_005518.4(HMGCS2):​c.1522G>T​(p.Val508Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,190 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V508I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: HMGCS2 NM_005518.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.18
• 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: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_005518.4
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.12692314).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGCS2	NM_005518.4	MANE Select	c.1522G>T	p.Val508Phe	missense	Exon 9 of 10	NP_005509.1	P54868-1
	HMGCS2	NM_001166107.1		c.1396G>T	p.Val466Phe	missense	Exon 8 of 9	NP_001159579.1	P54868-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGCS2	ENST00000369406.8	TSL:1 MANE Select	c.1522G>T	p.Val508Phe	missense	Exon 9 of 10	ENSP00000358414.3	P54868-1
	HMGCS2	ENST00000886233.1		c.1549G>T	p.Val517Phe	missense	Exon 10 of 11	ENSP00000556292.1
	HMGCS2	ENST00000886228.1		c.1522G>T	p.Val508Phe	missense	Exon 9 of 10	ENSP00000556287.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459190 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726144

African (AFR) AF: 0.00 AC: 0 AN: 33388

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109650

Other (OTH) AF: 0.00 AC: 0 AN: 60306

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	2.6
DANN	Uncertain	0.98
DEOGEN2	Benign	0.21	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.028	N
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	1.7	L
PhyloP100		-1.2
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.37
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.011	D
Polyphen		0.61	P
Vest4		0.15
MutPred		0.40		Gain of glycosylation at P507 (P = 0.07)
MVP		0.24
MPC		0.17
ClinPred		0.53	D
GERP RS		-7.8
Varity_R		0.090
gMVP		0.33
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs76773981; hg19: chr1-120293430;