Genetic Variant HMGCS1:p.Ala392Gly (chr5-43294064-G-C) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_001098272.3(HMGCS1):c.1175C>G(p.Ala392Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000702 in 1,592,958 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00049 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00072 ( 1 hom. )

Consequence

HMGCS1
NM_001098272.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.58

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.118227184).

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000486 (74/152112) while in subpopulation AMR AF= 0.000787 (12/15256). AF 95% confidence interval is 0.000599. There are 0 homozygotes in gnomad4. There are 35 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMGCS1	NM_001098272.3 link	c.1175C>G	p.Ala392Gly	missense_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.1175C>G	p.Ala392Gly	missense_variant	Exon 8 of 11	1	NM_001098272.3	ENSP00000322706.6	Q01581
HMGCS1	ENST00000433297.2 link	c.1175C>G	p.Ala392Gly	missense_variant	Exon 7 of 10	5		ENSP00000399402.2	Q01581
HMGCS1	ENST00000508319.1 link	n.261C>G		non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.000486

AC:

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000787

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000764

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.000446

AC:

112

AN:

251204

Hom.:

AF XY:

0.000471

AC XY:

AN XY:

135768

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000463

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000722

Gnomad OTH exome

AF:

0.000980

GnomAD4 exome

AF:

0.000725

AC:

1044

AN:

1440846

Hom.:

Cov.:

AF XY:

0.000704

AC XY:

506

AN XY:

718280

show subpopulations

Gnomad4 AFR exome

AF:

0.000302

Gnomad4 AMR exome

AF:

0.000492

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000749

Gnomad4 NFE exome

AF:

0.000877

Gnomad4 OTH exome

AF:

0.000804

GnomAD4 genome

AF:

0.000486

AC:

AN:

152112

Hom.:

Cov.:

AF XY:

0.000471

AC XY:

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.000787

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000764

Gnomad4 OTH

AF:

0.000955

Alfa

AF:

0.000785

Hom.:

Bravo

AF:

0.000684

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000420

AC:

EpiCase

AF:

0.000982

EpiControl

AF:

0.000652

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1175C>G (p.A392G) alteration is located in exon 8 (coding exon 6) of the HMGCS1 gene. This alteration results from a C to G substitution at nucleotide position 1175, causing the alanine (A) at amino acid position 392 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.54

D;D

Eigen

Benign

0.039

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.91

.;D

M_CAP

Benign

0.031

MetaRNN

Benign

0.12

T;T

MetaSVM

Benign

-0.53

MutationAssessor

Benign

1.8

L;L

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-2.3

N;N

REVEL

Uncertain

0.35

Sift

Benign

0.21

T;T

Sift4G

Benign

0.39

T;T

Polyphen

0.0020

B;B

Vest4

0.28

MVP

0.43

MPC

0.98

ClinPred

0.036

GERP RS

5.5

Varity_R

0.43

gMVP

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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