Variant 2-222934531-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_004457.5(ACSL3):c.1849T>C(p.Tyr617His) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000714 in 1,401,340 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. 3/3 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: 7.1e-7 ( 0 hom. )

Consequence

ACSL3
NM_004457.5 missense, splice_region

Scores

Splicing: ADA: 0.01243

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.53

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]

ACSL3 links:

ACSL3 (HGNC:):

ACSL3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.26794225).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACSL3	NM_004457.5 linkuse as main transcript	c.1849T>C	p.Tyr617His	missense_variant, splice_region_variant	16/17	ENST00000357430.8	NP_004448.2	O95573A0A024R487
ACSL3	NM_001354158.2 linkuse as main transcript	c.1849T>C	p.Tyr617His	missense_variant, splice_region_variant	15/16		NP_001341087.1
ACSL3	NM_001354159.2 linkuse as main transcript	c.1849T>C	p.Tyr617His	missense_variant, splice_region_variant	14/15		NP_001341088.1
ACSL3	NM_203372.3 linkuse as main transcript	c.1849T>C	p.Tyr617His	missense_variant, splice_region_variant	15/16		NP_976251.1	O95573A0A024R487

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACSL3	ENST00000357430.8 linkuse as main transcript	c.1849T>C	p.Tyr617His	missense_variant, splice_region_variant	16/17	1	NM_004457.5	ENSP00000350012.3		O95573

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000460

AC:

AN:

217334

Hom.:

AF XY:

0.00

AC XY:

AN XY:

117680

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:

0.00000975

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.14e-7

AC:

AN:

1401340

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

689412

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.25e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 12, 2021

The c.1849T>C (p.Y617H) alteration is located in exon 16 (coding exon 13) of the ACSL3 gene. This alteration results from a T to C substitution at nucleotide position 1849, causing the tyrosine (Y) at amino acid position 617 to be replaced by a histidine (H). 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

0.13

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.53

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.063

T;T

Eigen

Benign

0.11

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.84

.;T

M_CAP

Benign

0.0051

MetaRNN

Benign

0.27

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.78

N;N

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.73

N;N

REVEL

Benign

0.071

Sift

Benign

0.52

T;T

Sift4G

Benign

0.54

T;T

Polyphen

0.61

P;P

Vest4

0.38

MutPred

0.49

Loss of stability (P = 0.0813);Loss of stability (P = 0.0813);

MVP

0.41

MPC

2.0

ClinPred

0.38

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.052

gMVP

0.32

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.012

dbscSNV1_RF

Benign

0.15

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over