chr1-119748606-TTTCACAAA-T

Variant names:

• chr1-119748606-TTTCACAAA-T
• rs200828254
• NM_005518.4:c.*233_*240delTTTGTGAA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_005518.4(HMGCS2):​c.*233_*240delTTTGTGAA 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
• 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: Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet, ClinGen, G2P

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 39 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMGCS2	NM_005518.4	c.*233_*240delTTTGTGAA		3_prime_UTR_variant	Exon 10 of 10	ENST00000369406.8	NP_005509.1
HMGCS2	NM_001166107.1	c.*233_*240delTTTGTGAA		3_prime_UTR_variant	Exon 9 of 9		NP_001159579.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMGCS2	ENST00000369406.8	c.*233_*240delTTTGTGAA		3_prime_UTR_variant	Exon 10 of 10	1	NM_005518.4	ENSP00000358414.3
HMGCS2	ENST00000544913.2	c.*233_*240delTTTGTGAA		3_prime_UTR_variant	Exon 9 of 9	2		ENSP00000439495.2

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

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 26

Other (OTH) AF: 0.00 AC: 0 AN: 2

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

African (AFR) AF: 0.00424 AC: 176 AN: 41538

American (AMR) AF: 0.0143 AC: 218 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0786 AC: 273 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.0149 AC: 72 AN: 4820

European-Finnish (FIN) AF: 0.00762 AC: 81 AN: 10624

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0261 AC: 1774 AN: 68022

Other (OTH) AF: 0.0232 AC: 49 AN: 2114

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

Jul 24, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs200828254; hg19: chr1-120291229;