5-43292887-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_001098272.3(HMGCS1):​c.1270G>A​(p.Ala424Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000932 in 1,610,218 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

HMGCS1
NM_001098272.3 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.58
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.11783522).
BS1
Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.00000892 (13/1458114) while in subpopulation AFR AF= 0.00018 (6/33248). AF 95% confidence interval is 0.0000786. There are 0 homozygotes in gnomad4_exome. There are 4 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HMGCS1NM_001098272.3 linkc.1270G>A p.Ala424Thr missense_variant Exon 9 of 11 ENST00000325110.11 NP_001091742.1 Q01581A0A024R059

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HMGCS1ENST00000325110.11 linkc.1270G>A p.Ala424Thr missense_variant Exon 9 of 11 1 NM_001098272.3 ENSP00000322706.6 Q01581
HMGCS1ENST00000433297.2 linkc.1270G>A p.Ala424Thr missense_variant Exon 8 of 10 5 ENSP00000399402.2 Q01581

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152104
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000242
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000405
AC:
1
AN:
246748
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
133208
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000891
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000892
AC:
13
AN:
1458114
Hom.:
0
Cov.:
31
AF XY:
0.00000552
AC XY:
4
AN XY:
725212
show subpopulations
Gnomad4 AFR exome
AF:
0.000180
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000540
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152104
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74298
show subpopulations
Gnomad4 AFR
AF:
0.0000242
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000658
Hom.:
0
Bravo
AF:
0.0000151
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Apr 01, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1270G>A (p.A424T) alteration is located in exon 9 (coding exon 7) of the HMGCS1 gene. This alteration results from a G to A substitution at nucleotide position 1270, causing the alanine (A) at amino acid position 424 to be replaced by a threonine (T). 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
0.099
BayesDel_addAF
Benign
-0.12
T
BayesDel_noAF
Benign
-0.41
CADD
Benign
11
DANN
Benign
0.84
DEOGEN2
Benign
0.25
T;T
Eigen
Benign
-0.38
Eigen_PC
Benign
-0.14
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Benign
0.83
.;T
M_CAP
Benign
0.022
T
MetaRNN
Benign
0.12
T;T
MetaSVM
Benign
-0.85
T
MutationAssessor
Benign
0.86
L;L
PrimateAI
Benign
0.39
T
PROVEAN
Benign
0.10
N;N
REVEL
Benign
0.18
Sift
Benign
0.66
T;T
Sift4G
Benign
0.61
T;T
Polyphen
0.063
B;B
Vest4
0.081
MutPred
0.36
Gain of glycosylation at A424 (P = 0.0449);Gain of glycosylation at A424 (P = 0.0449);
MVP
0.32
MPC
0.94
ClinPred
0.24
T
GERP RS
4.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.4
Varity_R
0.10
gMVP
0.36

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs888852464; hg19: chr5-43292989; COSMIC: COSV57290046; COSMIC: COSV57290046; API