rs769998920

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PM2 PP2 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. 16/22 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
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• rigid spine syndrome

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 6 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 3.0389 (below the threshold of 3.09). Trascript score misZ: 4.1249 (above the threshold of 3.09). GenCC associations: The gene is linked to rigid spine syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.05950123).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001098272.3. 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
	HMGCS1	NM_001098272.3	MANE Select	c.1459A>G	p.Asn487Asp	missense	Exon 10 of 11	NP_001091742.1	Q01581
	HMGCS1	NM_001324219.2		c.1459A>G	p.Asn487Asp	missense	Exon 9 of 10	NP_001311148.1	Q01581
	HMGCS1	NM_001324220.2		c.1459A>G	p.Asn487Asp	missense	Exon 10 of 11	NP_001311149.1	Q01581

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGCS1	ENST00000325110.11	TSL:1 MANE Select	c.1459A>G	p.Asn487Asp	missense	Exon 10 of 11	ENSP00000322706.6	Q01581
	HMGCS1	ENST00000715988.1		c.1510A>G	p.Asn504Asp	missense	Exon 10 of 11	ENSP00000520550.1	A0ABB0MV10
	HMGCS1	ENST00000433297.2	TSL:5	c.1459A>G	p.Asn487Asp	missense	Exon 9 of 10	ENSP00000399402.2	Q01581

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000797 AC: 2 AN: 251096 AF XY: 0.00

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111786

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.34	N
PhyloP100		2.0
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.21
Sift	Benign	0.16	T
Sift4G	Benign	0.26	T
Polyphen		0.0090	B
Vest4		0.15
MutPred		0.26		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
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs769998920; hg19: chr5-43292590;