rs3790692

Positions:

• chr1-119767245-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005518.4(HMGCS2):​c.104+1496T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.352 in 152,038 control chromosomes in the GnomAD database, including 9,882 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.35 (9882 hom., cov: 32)
• Consequence: HMGCS2 NM_005518.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0370

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.405 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HMGCS2	NM_005518.4	c.104+1496T>C		intron_variant		ENST00000369406.8	NP_005509.1
HMGCS2	NM_001166107.1	c.104+1496T>C		intron_variant			NP_001159579.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HMGCS2	ENST00000369406.8	c.104+1496T>C		intron_variant		1	NM_005518.4	ENSP00000358414.3
HMGCS2	ENST00000544913.2	c.104+1496T>C		intron_variant		2		ENSP00000439495.2

Frequencies

GnomAD3 genomes AF: 0.352 AC: 53500 AN: 151920 Hom.: 9866 Cov.: 32

Gnomad AFR AF: 0.239

Gnomad AMI AF: 0.492

Gnomad AMR AF: 0.335

Gnomad ASJ AF: 0.386

Gnomad EAS AF: 0.361

Gnomad SAS AF: 0.269

Gnomad FIN AF: 0.470

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.409

Gnomad OTH AF: 0.335

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.352 AC: 53549 AN: 152038 Hom.: 9882 Cov.: 32 AF XY: 0.352 AC XY: 26139 AN XY: 74328

Gnomad4 AFR AF: 0.239

Gnomad4 AMR AF: 0.336

Gnomad4 ASJ AF: 0.386

Gnomad4 EAS AF: 0.362

Gnomad4 SAS AF: 0.269

Gnomad4 FIN AF: 0.470

Gnomad4 NFE AF: 0.409

Gnomad4 OTH AF: 0.336

Alfa AF: 0.386 Hom.: 16905

Bravo AF: 0.338

Asia WGS AF: 0.346 AC: 1203 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.7
DANN	Benign	0.44

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

Publications

LitVar

Other links and lift over

dbSNP: rs3790692; hg19: chr1-120309868;