1-119748606-TTTCACAAA-T

Position:

• chr1-119748606-TTTCACAAA-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_005518.4(HMGCS2):​c.*233_*240del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0175 in 152,278 control chromosomes in the GnomAD database, including 39 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.018 (39 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, single submitter B:1
• Conservation: PhyloP100: 1.33

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 -10 ACMG points.

• BP6: Variant 1-119748606-TTTCACAAA-T is Benign according to our data. Variant chr1-119748606-TTTCACAAA-T is described in ClinVar as [Likely_benign]. Clinvar id is 1203864.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0175 (2670/152278) while in subpopulation NFE AF= 0.0261 (1774/68022). AF 95% confidence interval is 0.0251. There are 39 homozygotes in gnomad4. There are 1214 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 39 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HMGCS2	NM_005518.4	c.*233_*240del		3_prime_UTR_variant	10/10	ENST00000369406.8	NP_005509.1
HMGCS2	NM_001166107.1	c.*233_*240del		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.*233_*240del		3_prime_UTR_variant	10/10	1	NM_005518.4	ENSP00000358414	P1
HMGCS2	ENST00000544913.2	c.*233_*240del		3_prime_UTR_variant	9/9	2		ENSP00000439495

Frequencies

GnomAD3 genomes AF: 0.0176 AC: 2671 AN: 152160 Hom.: 39 Cov.: 32

Gnomad AFR AF: 0.00425

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.0143

Gnomad ASJ AF: 0.0786

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0151

Gnomad FIN AF: 0.00762

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0261

Gnomad OTH AF: 0.0234

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 32 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 18

Gnomad4 AFR exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0175 AC: 2670 AN: 152278 Hom.: 39 Cov.: 32 AF XY: 0.0163 AC XY: 1214 AN XY: 74456

Gnomad4 AFR AF: 0.00424

Gnomad4 AMR AF: 0.0143

Gnomad4 ASJ AF: 0.0786

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0149

Gnomad4 FIN AF: 0.00762

Gnomad4 NFE AF: 0.0261

Gnomad4 OTH AF: 0.0232

Alfa AF: 0.0213 Hom.: 7

Bravo AF: 0.0179

Asia WGS AF: 0.00808 AC: 28 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 24, 2020

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs200828254; hg19: chr1-120291229;