chr1-119750807-C-T

Position:

• chr1-119750807-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_005518.4(HMGCS2):​c.1522G>A​(p.Val508Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00289 in 1,611,352 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (6 hom.)
• Consequence: HMGCS2 NM_005518.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -1.18

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0043078065).
• BP6: Variant 1-119750807-C-T is Benign according to our data. Variant chr1-119750807-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 292327.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00229 (349/152212) while in subpopulation NFE AF= 0.00382 (260/68014). AF 95% confidence interval is 0.00344. There are 1 homozygotes in gnomad4. There are 165 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HMGCS2	NM_005518.4	c.1522G>A	p.Val508Ile	missense_variant	9/10	ENST00000369406.8	NP_005509.1
HMGCS2	NM_001166107.1	c.1396G>A	p.Val466Ile	missense_variant	8/9		NP_001159579.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HMGCS2	ENST00000369406.8	c.1522G>A	p.Val508Ile	missense_variant	9/10	1	NM_005518.4	ENSP00000358414	P1
HMGCS2	ENST00000544913.2	c.1396G>A	p.Val466Ile	missense_variant	8/9	2		ENSP00000439495

Frequencies

GnomAD3 genomes AF: 0.00230 AC: 350 AN: 152094 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000773

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00384

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00188 AC: 472 AN: 251182 Hom.: 1 AF XY: 0.00189 AC XY: 256 AN XY: 135756

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.00795

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00302

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00295 AC: 4310 AN: 1459140 Hom.: 6 Cov.: 31 AF XY: 0.00294 AC XY: 2134 AN XY: 726118

Gnomad4 AFR exome AF: 0.000359

Gnomad4 AMR exome AF: 0.000693

Gnomad4 ASJ exome AF: 0.00735

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.000506

Gnomad4 NFE exome AF: 0.00345

Gnomad4 OTH exome AF: 0.00360

GnomAD4 genome AF: 0.00229 AC: 349 AN: 152212 Hom.: 1 Cov.: 32 AF XY: 0.00222 AC XY: 165 AN XY: 74422

Gnomad4 AFR AF: 0.000770

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.0104

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00382

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00323 Hom.: 0

Bravo AF: 0.00218

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00395 AC: 34

ExAC AF: 0.00181 AC: 220

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00327

EpiControl AF: 0.00338

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 12, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 18, 2018	The HMGCS2 c.1522G>A; p.Val508Ile variant (rs76773981), to our knowledge, is not reported in the medical literature; however it is listed in ClinVar as uncertain (Variation ID: 292327). This variant is found in the general population with an overall allele frequency of 0.19% (526/276,942 alleles, including 1 homozygotes) in the Genome Aggregation Database. The valine at codon 508 is moderately conserved but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Taken together, based on the available evidence, this the clinical significance of this variant is uncertain. -

3-hydroxy-3-methylglutaryl-CoA synthase deficiency 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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 01, 2024	- -

HMGCS2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 25, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	0.27
DANN	Benign	0.77
DEOGEN2	Benign	0.13	T;.
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.0043	T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.4	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.010	N;N
REVEL	Benign	0.10
Sift	Benign	0.38	T;T
Sift4G	Benign	0.62	T;T
Polyphen		0.0	B;.
Vest4		0.058
MVP		0.33
MPC		0.081
ClinPred		0.0043	T
GERP RS		-7.8
Varity_R		0.036
gMVP		0.074

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs76773981; hg19: chr1-120293430;