5-43292488-T-C

Variant names:

• chr5-43292488-T-C
• rs769998920
• NM_001098272.3:c.1459A>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001098272.3(HMGCS1):​c.1459A>G​(p.Asn487Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,544 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: HMGCS1 NM_001098272.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.98

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05950123).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMGCS1	NM_001098272.3	c.1459A>G	p.Asn487Asp	missense_variant	Exon 10 of 11	ENST00000325110.11	NP_001091742.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMGCS1	ENST00000325110.11	c.1459A>G	p.Asn487Asp	missense_variant	Exon 10 of 11	1	NM_001098272.3	ENSP00000322706.6
HMGCS1	ENST00000433297.2	c.1459A>G	p.Asn487Asp	missense_variant	Exon 9 of 10	5		ENSP00000399402.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 251096 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135734

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461544 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727060

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1459A>G (p.N487D) alteration is located in exon 10 (coding exon 8) of the HMGCS1 gene. This alteration results from a A to G substitution at nucleotide position 1459, causing the asparagine (N) at amino acid position 487 to be replaced by an aspartic acid (D). 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	0.054
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T;T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.78	.;T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.060	T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.34	N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.39	N;N
REVEL	Benign	0.21
Sift	Benign	0.16	T;T
Sift4G	Benign	0.26	T;T
Polyphen		0.0090	B;B
Vest4		0.15
MutPred		0.26		Gain of catalytic residue at N487 (P = 0.054);Gain of catalytic residue at N487 (P = 0.054);
MVP		0.44
MPC		0.095
ClinPred		0.18	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.045
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
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

LitVar

Other links and lift over

dbSNP: rs769998920; hg19: chr5-43292590;