Genetic Variant NM_005518.4:c.1419G>A (chr1-119752550-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_005518.4(HMGCS2):c.1419G>A(p.Lys473Lys) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00497 in 1,613,912 control chromosomes in the GnomAD database, including 149 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0034 ( 11 hom., cov: 32)

Exomes 𝑓: 0.0051 ( 138 hom. )

Consequence

HMGCS2
NM_005518.4 splice_region, synonymous

Scores

Splicing: ADA: 0.0002780

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.290

Publications

3 publications found

Variant links:

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

HMGCS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

BP6

Variant 1-119752550-C-T is Benign according to our data. Variant chr1-119752550-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 292330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.29 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00345 (525/152258) while in subpopulation SAS AF = 0.0386 (186/4816). AF 95% confidence interval is 0.0341. There are 11 homozygotes in GnomAd4. There are 306 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 11 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005518.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGCS2	NM_005518.4	MANE Select	c.1419G>A	p.Lys473Lys	splice_region synonymous	Exon 8 of 10	NP_005509.1
	HMGCS2	NM_001166107.1		c.1293G>A	p.Lys431Lys	splice_region synonymous	Exon 7 of 9	NP_001159579.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HMGCS2	ENST00000369406.8	TSL:1 MANE Select	c.1419G>A	p.Lys473Lys	splice_region synonymous	Exon 8 of 10	ENSP00000358414.3
HMGCS2	ENST00000886233.1		c.1446G>A	p.Lys482Lys	splice_region synonymous	Exon 9 of 11	ENSP00000556292.1
HMGCS2	ENST00000886228.1		c.1419G>A	p.Lys473Lys	splice_region synonymous	Exon 8 of 10	ENSP00000556287.1

Frequencies

GnomAD3 genomes

AF:

0.00346

AC:

526

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000603

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00334

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0388

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.00322

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00797

AC:

2004

AN:

251474

AF XY:

0.0101

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.00335

Gnomad ASJ exome

AF:

0.00516

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.000878

Gnomad NFE exome

AF:

0.00373

Gnomad OTH exome

AF:

0.00750

GnomAD4 exome

AF:

0.00513

AC:

7503

AN:

1461654

Hom.:

138

Cov.:

AF XY:

0.00646

AC XY:

4694

AN XY:

727112

show subpopulations

African (AFR)

AF:

0.00108

AC:

AN:

33478

American (AMR)

AF:

0.00295

AC:

132

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00528

AC:

138

AN:

26130

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.0442

AC:

3810

AN:

86236

European-Finnish (FIN)

AF:

0.00118

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.0413

AC:

238

AN:

5764

European-Non Finnish (NFE)

AF:

0.00246

AC:

2739

AN:

1111868

Other (OTH)

AF:

0.00573

AC:

346

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

414

829

1243

1658

2072

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

118

236

354

472

590

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00345

AC:

525

AN:

152258

Hom.:

Cov.:

AF XY:

0.00411

AC XY:

306

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.000602

AC:

AN:

41550

American (AMR)

AF:

0.00334

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5190

South Asian (SAS)

AF:

0.0386

AC:

186

AN:

4816

European-Finnish (FIN)

AF:

0.00104

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00322

AC:

219

AN:

68024

Other (OTH)

AF:

0.00284

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

112

140

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00390

Hom.:

Bravo

AF:

0.00247

Asia WGS

AF:

0.0180

AC:

AN:

3478

EpiCase

AF:

0.00534

EpiControl

AF:

0.00486

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

3-hydroxy-3-methylglutaryl-CoA synthase deficiency (4)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

5.7

(source)

DANN

Benign

0.78

PhyloP100

-0.29

Mutation Taster

=88/12

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00028

dbscSNV1_RF

Benign

0.10

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over