1-119748515-T-G

Position:

• chr1-119748515-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005518.4(HMGCS2):​c.*332A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0242 in 152,332 control chromosomes in the GnomAD database, including 144 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (144 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HMGCS2 NM_005518.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.293

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 1-119748515-T-G is Benign according to our data. Variant chr1-119748515-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 292323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0807 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HMGCS2	NM_005518.4	c.*332A>C		3_prime_UTR_variant	10/10	ENST00000369406.8	NP_005509.1
HMGCS2	NM_001166107.1	c.*332A>C		3_prime_UTR_variant	9/9		NP_001159579.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HMGCS2	ENST00000369406.8	c.*332A>C		3_prime_UTR_variant	10/10	1	NM_005518.4	ENSP00000358414	P1
HMGCS2	ENST00000544913.2	c.*332A>C		3_prime_UTR_variant	9/9	2		ENSP00000439495

Frequencies

GnomAD3 genomes AF: 0.0242 AC: 3681 AN: 152214 Hom.: 143 Cov.: 32

Gnomad AFR AF: 0.0829

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0112

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.0191

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 18 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 10

Gnomad4 NFE exome AF: 0.00

GnomAD4 genome AF: 0.0242 AC: 3694 AN: 152332 Hom.: 144 Cov.: 32 AF XY: 0.0231 AC XY: 1718 AN XY: 74500

Gnomad4 AFR AF: 0.0830

Gnomad4 AMR AF: 0.0112

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000426

Gnomad4 OTH AF: 0.0189

Alfa AF: 0.0102 Hom.: 9

Bravo AF: 0.0275

Asia WGS AF: 0.00866 AC: 31 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PHGDH deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Likely 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	-0.85
CADD	Benign	0.45
DANN	Benign	0.71

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: rs56828380; hg19: chr1-120291138;