NM_001098272.3:c.645A>G

Variant names:

• chr5-43297096-T-C
• rs1478056967
• NM_001098272.3:c.645A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 3P and 3B. PM2 PP2 BP4_Moderate BS1_Supporting

The NM_001098272.3(HMGCS1):​c.645A>G​(p.Ile215Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,356 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: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: HMGCS1 NM_001098272.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.448
• 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: Uncertain_significance. The variant received 0 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=0.19876993).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000046 (7/152224) while in subpopulation AFR AF = 0.000169 (7/41466). AF 95% confidence interval is 0.0000789. There are 0 homozygotes in GnomAd4. There are 6 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.645A>G	p.Ile215Met	missense	Exon 5 of 11	NP_001091742.1	Q01581
	HMGCS1	NM_001324219.2		c.645A>G	p.Ile215Met	missense	Exon 4 of 10	NP_001311148.1	Q01581
	HMGCS1	NM_001324220.2		c.645A>G	p.Ile215Met	missense	Exon 5 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.645A>G	p.Ile215Met	missense	Exon 5 of 11	ENSP00000322706.6	Q01581
	HMGCS1	ENST00000715988.1		c.696A>G	p.Ile232Met	missense	Exon 5 of 11	ENSP00000520550.1	A0ABB0MV10
	HMGCS1	ENST00000433297.2	TSL:5	c.645A>G	p.Ile215Met	missense	Exon 4 of 10	ENSP00000399402.2	Q01581

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461132 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726914

African (AFR) AF: 0.000120 AC: 4 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111352

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152224 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74366

African (AFR) AF: 0.000169 AC: 7 AN: 41466

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000340

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	0.085
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.42	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.41	N
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.66	N
PhyloP100		-0.45
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.21
Sift	Uncertain	0.029	D
Sift4G	Uncertain	0.054	T
Polyphen		0.0010	B
Vest4		0.19
MutPred		0.62		Loss of catalytic residue at I215 (P = 0.0828)
MVP		0.25
MPC		0.99
ClinPred		0.24	T
GERP RS		0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.84
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

dbSNP: rs1478056967; hg19: chr5-43297198;