2-222908805-C-T

Variant names:

• chr2-222908805-C-T
• rs146044900
• NM_004457.5:c.33C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_004457.5(ACSL3):​c.33C>T​(p.Thr11Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00412 in 1,602,950 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (36 hom.)
• Consequence: ACSL3 NM_004457.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.391
• Publications: 4 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]

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 2-222908805-C-T is Benign according to our data. Variant chr2-222908805-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 712051.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.391 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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.33C>T	p.Thr11Thr	synonymous	Exon 4 of 17	NP_004448.2
	ACSL3	NM_001354158.2		c.33C>T	p.Thr11Thr	synonymous	Exon 3 of 16	NP_001341087.1	O95573
	ACSL3	NM_001354159.2		c.33C>T	p.Thr11Thr	synonymous	Exon 2 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.33C>T	p.Thr11Thr	synonymous	Exon 4 of 17	ENSP00000350012.3	O95573
	ACSL3	ENST00000903386.1		c.33C>T	p.Thr11Thr	synonymous	Exon 2 of 15	ENSP00000573445.1
	ACSL3	ENST00000392066.7	TSL:5	c.33C>T	p.Thr11Thr	synonymous	Exon 3 of 16	ENSP00000375918.3	O95573

Frequencies

GnomAD3 genomes AF: 0.00385 AC: 585 AN: 152130 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00720

Gnomad ASJ AF: 0.0369

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00432

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00459 AC: 1108 AN: 241584 AF XY: 0.00471

Gnomad AFR exome AF: 0.000396

Gnomad AMR exome AF: 0.00340

Gnomad ASJ exome AF: 0.0395

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000278

Gnomad NFE exome AF: 0.00468

Gnomad OTH exome AF: 0.00829

GnomAD4 exome AF: 0.00415 AC: 6014 AN: 1450704 Hom.: 36 Cov.: 31 AF XY: 0.00426 AC XY: 3075 AN XY: 721188

African (AFR) AF: 0.000796 AC: 26 AN: 32672

American (AMR) AF: 0.00349 AC: 147 AN: 42072

Ashkenazi Jewish (ASJ) AF: 0.0385 AC: 999 AN: 25964

East Asian (EAS) AF: 0.00 AC: 0 AN: 39394

South Asian (SAS) AF: 0.000879 AC: 73 AN: 83090

European-Finnish (FIN) AF: 0.000450 AC: 24 AN: 53292

Middle Eastern (MID) AF: 0.0162 AC: 85 AN: 5256

European-Non Finnish (NFE) AF: 0.00387 AC: 4296 AN: 1109012

Other (OTH) AF: 0.00607 AC: 364 AN: 59952

GnomAD4 genome AF: 0.00383 AC: 583 AN: 152246 Hom.: 2 Cov.: 32 AF XY: 0.00402 AC XY: 299 AN XY: 74442

African (AFR) AF: 0.000722 AC: 30 AN: 41552

American (AMR) AF: 0.00713 AC: 109 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0369 AC: 128 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4818

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10592

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00432 AC: 294 AN: 68020

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.00642 Hom.: 2

Bravo AF: 0.00445

Asia WGS AF: 0.000289 AC: 1 AN: 3474

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	9.6
DANN	Benign	0.83
PhyloP100		0.39
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	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: rs146044900; hg19: chr2-223773523; COSMIC: COSV62483583;