12-7306684-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001080454.2(ACSM4):​c.353C>T​(p.Ala118Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000114 in 1,611,134 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 0.000072 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

ACSM4
NM_001080454.2 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.30
Variant links:
Genes affected
ACSM4 (HGNC:32016): (acyl-CoA synthetase medium chain family member 4) Predicted to enable decanoate-CoA ligase activity and fatty-acyl-CoA synthase activity. Predicted to be involved in acyl-CoA metabolic process and fatty acid biosynthetic process. Predicted to be active in mitochondrial matrix. [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 -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.033711016).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ACSM4NM_001080454.2 linkc.353C>T p.Ala118Val missense_variant Exon 2 of 13 ENST00000399422.5 NP_001073923.1 P0C7M7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ACSM4ENST00000399422.5 linkc.353C>T p.Ala118Val missense_variant Exon 2 of 13 5 NM_001080454.2 ENSP00000382349.4 P0C7M7

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152044
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:
0.000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000614
AC:
15
AN:
244388
Hom.:
0
AF XY:
0.0000680
AC XY:
9
AN XY:
132364
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:
0.000135
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000119
AC:
173
AN:
1459090
Hom.:
0
Cov.:
32
AF XY:
0.000121
AC XY:
88
AN XY:
725442
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000225
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:
0.000152
Gnomad4 OTH exome
AF:
0.0000498
GnomAD4 genome
AF:
0.0000723
AC:
11
AN:
152044
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74236
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:
0.000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000165
Hom.:
0
Bravo
AF:
0.000113
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.000778
AC:
3
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000118
AC:
1
ExAC
AF:
0.0000908
AC:
11

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Oct 28, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.353C>T (p.A118V) alteration is located in exon 2 (coding exon 2) of the ACSM4 gene. This alteration results from a C to T substitution at nucleotide position 353, causing the alanine (A) at amino acid position 118 to be replaced by a valine (V). 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
0.095
BayesDel_addAF
Benign
-0.34
T
BayesDel_noAF
Benign
-0.47
CADD
Benign
13
DANN
Benign
0.78
DEOGEN2
Benign
0.013
T
Eigen
Benign
-0.69
Eigen_PC
Benign
-0.63
FATHMM_MKL
Benign
0.041
N
LIST_S2
Benign
0.80
T
M_CAP
Benign
0.0075
T
MetaRNN
Benign
0.034
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.5
L
PrimateAI
Benign
0.35
T
PROVEAN
Benign
1.3
N
REVEL
Benign
0.057
Sift
Benign
1.0
T
Sift4G
Benign
0.89
T
Polyphen
0.0090
B
Vest4
0.20
MVP
0.21
MPC
0.076
ClinPred
0.023
T
GERP RS
0.93
Varity_R
0.054
gMVP
0.61

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs201159594; hg19: chr12-7459280; API