NM_001098272.3:c.1149G>A

Variant names:

• chr5-43294090-C-T
• rs56257144
• NM_001098272.3:c.1149G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

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 (★★). Synonymous variant affecting the same amino acid position (i.e. L383L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.086 (766 hom., cov: 31)
  • Exomes 𝑓: 0.11 (10454 hom.)
• Consequence: HMGCS1 NM_001098272.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0660
• Publications: 10 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: Benign. The variant received -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 VariationId 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.

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.1149G>A	p.Leu383Leu	synonymous	Exon 8 of 11	NP_001091742.1	Q01581
	HMGCS1	NM_001324219.2		c.1149G>A	p.Leu383Leu	synonymous	Exon 7 of 10	NP_001311148.1	Q01581
	HMGCS1	NM_001324220.2		c.1149G>A	p.Leu383Leu	synonymous	Exon 8 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.1149G>A	p.Leu383Leu	synonymous	Exon 8 of 11	ENSP00000322706.6	Q01581
	HMGCS1	ENST00000715988.1		c.1200G>A	p.Leu400Leu	synonymous	Exon 8 of 11	ENSP00000520550.1	A0ABB0MV10
	HMGCS1	ENST00000433297.2	TSL:5	c.1149G>A	p.Leu383Leu	synonymous	Exon 7 of 10	ENSP00000399402.2	Q01581

Frequencies

GnomAD3 genomes AF: 0.0866 AC: 13164 AN: 151984 Hom.: 771 Cov.: 31

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

GnomAD2 exomes AF: 0.0941 AC: 23654 AN: 251278 AF XY: 0.0995

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 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.: 29 AF XY: 0.114 AC XY: 82887 AN XY: 725804

African (AFR) AF: 0.0324 AC: 1083 AN: 33440

American (AMR) AF: 0.0644 AC: 2878 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 2757 AN: 26118

East Asian (EAS) AF: 0.000831 AC: 33 AN: 39694

South Asian (SAS) AF: 0.109 AC: 9430 AN: 86196

European-Finnish (FIN) AF: 0.0803 AC: 4287 AN: 53412

Middle Eastern (MID) AF: 0.183 AC: 1051 AN: 5750

European-Non Finnish (NFE) AF: 0.125 AC: 138202 AN: 1108878

Other (OTH) AF: 0.112 AC: 6775 AN: 60296

GnomAD4 genome AF: 0.0864 AC: 13148 AN: 152102 Hom.: 766 Cov.: 31 AF XY: 0.0839 AC XY: 6237 AN XY: 74350

African (AFR) AF: 0.0327 AC: 1356 AN: 41504

American (AMR) AF: 0.0768 AC: 1172 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 368 AN: 3468

East Asian (EAS) AF: 0.00232 AC: 12 AN: 5178

South Asian (SAS) AF: 0.114 AC: 549 AN: 4808

European-Finnish (FIN) AF: 0.0737 AC: 780 AN: 10584

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.125 AC: 8509 AN: 67986

Other (OTH) AF: 0.105 AC: 223 AN: 2114

Alfa AF: 0.104 Hom.: 654

Bravo AF: 0.0830

Asia WGS AF: 0.0510 AC: 176 AN: 3478

EpiCase AF: 0.129

EpiControl AF: 0.125

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	4.9
DANN	Benign	0.71
PhyloP100		0.066
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism (auto)

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: rs56257144; hg19: chr5-43294192;