2-222919191-A-G

Variant names:

• chr2-222919191-A-G
• rs144556995
• NM_004457.5:c.794A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_004457.5(ACSL3):​c.794A>G​(p.Lys265Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000317 in 1,614,038 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 29)
  • Exomes 𝑓: 0.00016 (1 hom.)
• Consequence: ACSL3 NM_004457.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.14
• Publications: 1 publications found

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-AS1 (HGNC:40227): (ACSL3 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004623145).
• BP6: Variant 2-222919191-A-G is Benign according to our data. Variant chr2-222919191-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 724724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004457.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACSL3	NM_004457.5	MANE Select	c.794A>G	p.Lys265Arg	missense	Exon 7 of 17	NP_004448.2
	ACSL3	NM_001354158.2		c.794A>G	p.Lys265Arg	missense	Exon 6 of 16	NP_001341087.1	O95573
	ACSL3	NM_001354159.2		c.794A>G	p.Lys265Arg	missense	Exon 5 of 15	NP_001341088.1	O95573

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACSL3	ENST00000357430.8	TSL:1 MANE Select	c.794A>G	p.Lys265Arg	missense	Exon 7 of 17	ENSP00000350012.3	O95573
	ACSL3	ENST00000903386.1		c.794A>G	p.Lys265Arg	missense	Exon 5 of 15	ENSP00000573445.1
	ACSL3	ENST00000392066.7	TSL:5	c.794A>G	p.Lys265Arg	missense	Exon 6 of 16	ENSP00000375918.3	O95573

Frequencies

GnomAD3 genomes AF: 0.00183 AC: 279 AN: 152168 Hom.: 1 Cov.: 29

Gnomad AFR AF: 0.00654

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

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: 0.000478

GnomAD2 exomes AF: 0.000422 AC: 106 AN: 251072 AF XY: 0.000280

Gnomad AFR exome AF: 0.00591

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000159 AC: 233 AN: 1461752 Hom.: 1 Cov.: 31 AF XY: 0.000147 AC XY: 107 AN XY: 727182

African (AFR) AF: 0.00586 AC: 196 AN: 33472

American (AMR) AF: 0.000470 AC: 21 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111924

Other (OTH) AF: 0.000232 AC: 14 AN: 60388

GnomAD4 genome AF: 0.00183 AC: 279 AN: 152286 Hom.: 1 Cov.: 29 AF XY: 0.00183 AC XY: 136 AN XY: 74464

African (AFR) AF: 0.00652 AC: 271 AN: 41572

American (AMR) AF: 0.000392 AC: 6 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68016

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000730 Hom.: 1

Bravo AF: 0.00204

ESP6500AA AF: 0.00386 AC: 17

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000560 AC: 68

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.047	T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.099
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		6.1
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.034
Sift	Benign	0.40	T
Sift4G	Benign	0.48	T
Polyphen		0.020	B
Vest4		0.41
MVP		0.55
MPC		0.18
ClinPred		0.024	T
GERP RS		5.3
Varity_R		0.16
gMVP		0.51
Mutation Taster		=74/26	polymorphism

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

Other links and lift over

dbSNP: rs144556995; hg19: chr2-223783909;