Genetic Variant HMGCS1:p.Leu383Leu (chr5-43294090-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001098272.3(HMGCS1):c.1149G>A(p.Leu383Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.112 in 1,610,592 control chromosomes in the GnomAD database, including 11,220 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.086 ( 766 hom., cov: 31)

Exomes 𝑓: 0.11 ( 10454 hom. )

Consequence

HMGCS1
NM_001098272.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0660

Variant links:

Genes affected

HMGCS1 (HGNC:5007): (3-hydroxy-3-methylglutaryl-CoA synthase 1) Enables protein homodimerization activity. Predicted to be involved in acetyl-CoA metabolic process and farnesyl diphosphate biosynthetic process, mevalonate pathway. Predicted to be located in cytoplasm. Predicted to be active in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

HMGCS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.35).

BP6

Variant 5-43294090-C-T is Benign according to our data. Variant chr5-43294090-C-T is described in ClinVar as [Benign]. Clinvar id is 1259973.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.066 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMGCS1	NM_001098272.3 link	c.1149G>A	p.Leu383Leu	synonymous_variant	Exon 8 of 11	ENST00000325110.11	NP_001091742.1	Q01581A0A024R059

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HMGCS1	ENST00000325110.11 link	c.1149G>A	p.Leu383Leu	synonymous_variant	Exon 8 of 11	1	NM_001098272.3	ENSP00000322706.6	Q01581
HMGCS1	ENST00000433297.2 link	c.1149G>A	p.Leu383Leu	synonymous_variant	Exon 7 of 10	5		ENSP00000399402.2	Q01581
HMGCS1	ENST00000508319.1 link	n.235G>A		non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.0866

AC:

13164

AN:

151984

Hom.:

771

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0327

Gnomad AMI

AF:

0.121

Gnomad AMR

AF:

0.0769

Gnomad ASJ

AF:

0.106

Gnomad EAS

AF:

0.00231

Gnomad SAS

AF:

0.116

Gnomad FIN

AF:

0.0737

Gnomad MID

AF:

0.253

Gnomad NFE

AF:

0.125

Gnomad OTH

AF:

0.106

GnomAD3 exomes

AF:

0.0941

AC:

23654

AN:

251278

Hom.:

1335

AF XY:

0.0995

AC XY:

13510

AN XY:

135806

show subpopulations

Gnomad AFR exome

AF:

0.0332

Gnomad AMR exome

AF:

0.0623

Gnomad ASJ exome

AF:

0.105

Gnomad EAS exome

AF:

0.00152

Gnomad SAS exome

AF:

0.109

Gnomad FIN exome

AF:

0.0808

Gnomad NFE exome

AF:

0.124

Gnomad OTH exome

AF:

0.112

GnomAD4 exome

AF:

0.114

AC:

166496

AN:

1458490

Hom.:

10454

Cov.:

AF XY:

0.114

AC XY:

82887

AN XY:

725804

show subpopulations

Gnomad4 AFR exome

AF:

0.0324

Gnomad4 AMR exome

AF:

0.0644

Gnomad4 ASJ exome

AF:

0.106

Gnomad4 EAS exome

AF:

0.000831

Gnomad4 SAS exome

AF:

0.109

Gnomad4 FIN exome

AF:

0.0803

Gnomad4 NFE exome

AF:

0.125

Gnomad4 OTH exome

AF:

0.112

GnomAD4 genome

AF:

0.0864

AC:

13148

AN:

152102

Hom.:

766

Cov.:

AF XY:

0.0839

AC XY:

6237

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.0327

Gnomad4 AMR

AF:

0.0768

Gnomad4 ASJ

AF:

0.106

Gnomad4 EAS

AF:

0.00232

Gnomad4 SAS

AF:

0.114

Gnomad4 FIN

AF:

0.0737

Gnomad4 NFE

AF:

0.125

Gnomad4 OTH

AF:

0.105

Alfa

AF:

0.108

Hom.:

542

Bravo

AF:

0.0830

Asia WGS

AF:

0.0510

AC:

176

AN:

3478

EpiCase

AF:

0.129

EpiControl

AF:

0.125

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 24, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 28171541) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.35

CADD

Benign

4.9

DANN

Benign

0.71

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over