2-222927019-T-C

Position:

• chr2-222927019-T-C

Variant summary

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

The NM_004457.5(ACSL3):​c.1295T>C​(p.Phe432Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,458,598 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ACSL3 NM_004457.5 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02

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]

ACMG classification

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/exons	MANE	Protein	UniProt
ACSL3	NM_004457.5	c.1295T>C	p.Phe432Ser	missense_variant, splice_region_variant	12/17	ENST00000357430.8	NP_004448.2
ACSL3	NM_001354158.2	c.1295T>C	p.Phe432Ser	missense_variant, splice_region_variant	11/16		NP_001341087.1
ACSL3	NM_001354159.2	c.1295T>C	p.Phe432Ser	missense_variant, splice_region_variant	10/15		NP_001341088.1
ACSL3	NM_203372.3	c.1295T>C	p.Phe432Ser	missense_variant, splice_region_variant	11/16		NP_976251.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACSL3	ENST00000357430.8	c.1295T>C	p.Phe432Ser	missense_variant, splice_region_variant	12/17	1	NM_004457.5	ENSP00000350012.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1458598 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725118

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 04, 2022

The c.1295T>C (p.F432S) alteration is located in exon 12 (coding exon 9) of the ACSL3 gene. This alteration results from a T to C substitution at nucleotide position 1295, causing the phenylalanine (F) at amino acid position 432 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	0.57
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.069	T;T
Eigen	Benign	0.068
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.90	.;D
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.74	D;D
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.89	L;L
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.5	D;D
REVEL	Benign	0.23
Sift	Benign	0.045	D;D
Sift4G	Uncertain	0.046	D;D
Polyphen		0.031	B;B
Vest4		0.71
MutPred		0.70		Gain of disorder (P = 0.036);Gain of disorder (P = 0.036);
MVP		0.12
MPC		0.62
ClinPred		0.91	D
GERP RS		5.9
Varity_R		0.50
gMVP		0.89

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-223791737;