2-222922811-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004457.5(ACSL3):​c.1060C>T​(p.Pro354Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,614,050 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

ACSL3
NM_004457.5 missense

Scores

7
7
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.99
Variant links:
Genes affected
ACSL3 (HGNC:3570): (acyl-CoA synthetase long chain family member 3) The protein encoded by this gene is an isozyme of the long-chain fatty-acid-coenzyme A ligase family. Although differing in substrate specificity, subcellular localization, and tissue distribution, all isozymes of this family convert free long-chain fatty acids into fatty acyl-CoA esters, and thereby play a key role in lipid biosynthesis and fatty acid degradation. This isozyme is highly expressed in brain, and preferentially utilizes myristate, arachidonate, and eicosapentaenoate as substrates. The amino acid sequence of this isozyme is 92% identical to that of rat homolog. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ACSL3NM_004457.5 linkc.1060C>T p.Pro354Ser missense_variant Exon 9 of 17 ENST00000357430.8 NP_004448.2 O95573A0A024R487
ACSL3NM_001354158.2 linkc.1060C>T p.Pro354Ser missense_variant Exon 8 of 16 NP_001341087.1
ACSL3NM_001354159.2 linkc.1060C>T p.Pro354Ser missense_variant Exon 7 of 15 NP_001341088.1
ACSL3NM_203372.3 linkc.1060C>T p.Pro354Ser missense_variant Exon 8 of 16 NP_976251.1 O95573A0A024R487

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ACSL3ENST00000357430.8 linkc.1060C>T p.Pro354Ser missense_variant Exon 9 of 17 1 NM_004457.5 ENSP00000350012.3 O95573

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152216
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.00000796
AC:
2
AN:
251320
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135828
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:
0.00000880
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.00000410
AC:
6
AN:
1461834
Hom.:
0
Cov.:
29
AF XY:
0.00000138
AC XY:
1
AN XY:
727220
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152216
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74362
show subpopulations
Gnomad4 AFR
AF:
0.0000241
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
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.00000824
AC:
1

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Feb 22, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1060C>T (p.P354S) alteration is located in exon 9 (coding exon 6) of the ACSL3 gene. This alteration results from a C to T substitution at nucleotide position 1060, causing the proline (P) at amino acid position 354 to be replaced by a serine (S). 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
Pathogenic
0.68
BayesDel_addAF
Uncertain
0.092
D
BayesDel_noAF
Benign
-0.10
CADD
Pathogenic
28
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.17
T;T
Eigen
Pathogenic
0.69
Eigen_PC
Uncertain
0.65
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
.;D
M_CAP
Benign
0.027
D
MetaRNN
Uncertain
0.72
D;D
MetaSVM
Benign
-0.67
T
MutationAssessor
Pathogenic
3.0
M;M
PrimateAI
Uncertain
0.76
T
PROVEAN
Pathogenic
-6.3
D;D
REVEL
Uncertain
0.34
Sift
Uncertain
0.023
D;D
Sift4G
Uncertain
0.027
D;D
Polyphen
1.0
D;D
Vest4
0.69
MVP
0.44
MPC
0.82
ClinPred
0.98
D
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.75
gMVP
0.82

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: rs377743525; hg19: chr2-223787529; API