chr5-43298880-T-A

Position:

• chr5-43298880-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_001098272.3(HMGCS1):​c.86A>T​(p.Gln29Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HMGCS1 NM_001098272.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.92

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.801
• PP5: Variant 5-43298880-T-A is Pathogenic according to our data. Variant chr5-43298880-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 2580363.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HMGCS1	NM_001098272.3	c.86A>T	p.Gln29Leu	missense_variant	3/11	ENST00000325110.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HMGCS1	ENST00000325110.11	c.86A>T	p.Gln29Leu	missense_variant	3/11	1	NM_001098272.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rigid spine syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Harry Perkins Institute Of Medical Research, University Of Western Australia

Sep 20, 2023

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.80	D;D;.
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Benign	0.053	D
MetaRNN	Pathogenic	0.80	D;D;D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Benign	0.80	N;N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-4.2	D;D;D
REVEL	Pathogenic	0.67
Sift	Benign	0.074	T;T;T
Sift4G	Benign	0.21	T;T;.
Polyphen		0.39	B;B;.
Vest4		0.66
MutPred		0.64		Loss of disorder (P = 0.083);Loss of disorder (P = 0.083);Loss of disorder (P = 0.083);
MVP		0.84
MPC		1.1
ClinPred		0.95	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.51
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1754165557; hg19: chr5-43298982;