5-43294090-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

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 (★★).

Frequency

Genomes: 𝑓 0.086 ( 766 hom., cov: 31)
Exomes 𝑓: 0.11 ( 10454 hom. )

Consequence

HMGCS1
NM_001098272.3 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0660
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 Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HMGCS1NM_001098272.3 linkc.1149G>A p.Leu383Leu synonymous_variant Exon 8 of 11 ENST00000325110.11 NP_001091742.1 Q01581A0A024R059

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HMGCS1ENST00000325110.11 linkc.1149G>A p.Leu383Leu synonymous_variant Exon 8 of 11 1 NM_001098272.3 ENSP00000322706.6 Q01581
HMGCS1ENST00000433297.2 linkc.1149G>A p.Leu383Leu synonymous_variant Exon 7 of 10 5 ENSP00000399402.2 Q01581
HMGCS1ENST00000508319.1 linkn.235G>A non_coding_transcript_exon_variant Exon 2 of 2 3

Frequencies

GnomAD3 genomes
AF:
0.0866
AC:
13164
AN:
151984
Hom.:
771
Cov.:
31
show subpopulations
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
GnomAD3 exomes
AF:
0.0941
AC:
23654
AN:
251278
Hom.:
1335
AF XY:
0.0995
AC XY:
13510
AN XY:
135806
show subpopulations
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 SAS exome
AF:
0.109
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
show subpopulations
Gnomad4 AFR exome
AF:
0.0324
Gnomad4 AMR exome
AF:
0.0644
Gnomad4 ASJ exome
AF:
0.106
Gnomad4 EAS exome
AF:
0.000831
Gnomad4 SAS exome
AF:
0.109
Gnomad4 FIN exome
AF:
0.0803
Gnomad4 NFE exome
AF:
0.125
Gnomad4 OTH exome
AF:
0.112
GnomAD4 genome
AF:
0.0864
AC:
13148
AN:
152102
Hom.:
766
Cov.:
31
AF XY:
0.0839
AC XY:
6237
AN XY:
74350
show subpopulations
Gnomad4 AFR
AF:
0.0327
Gnomad4 AMR
AF:
0.0768
Gnomad4 ASJ
AF:
0.106
Gnomad4 EAS
AF:
0.00232
Gnomad4 SAS
AF:
0.114
Gnomad4 FIN
AF:
0.0737
Gnomad4 NFE
AF:
0.125
Gnomad4 OTH
AF:
0.105
Alfa
AF:
0.108
Hom.:
542
Bravo
AF:
0.0830
Asia WGS
AF:
0.0510
AC:
176
AN:
3478
EpiCase
AF:
0.129
EpiControl
AF:
0.125

ClinVar

Significance: Benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
-
Breakthrough Genomics, Breakthrough Genomics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Feb 24, 2021
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 28171541) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.35
CADD
Benign
4.9
DANN
Benign
0.71
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

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

Publications

LitVar

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

Other links and lift over

dbSNP: rs56257144; hg19: chr5-43294192; API