5-131966431-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_001009185.3(ACSL6):c.1698C>T(p.Ile566=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000342 in 1,614,118 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (1 hom.)
• Consequence: ACSL6 NM_001009185.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.240

Genes affected

ACSL6 (HGNC:16496): (acyl-CoA synthetase long chain family member 6) The protein encoded by this gene catalyzes the formation of acyl-CoA from fatty acids, ATP, and CoA, using magnesium as a cofactor. The encoded protein plays a major role in fatty acid metabolism in the brain. Translocations with the ETV6 gene are causes of myelodysplastic syndrome with basophilia, acute myelogenous leukemia with eosinophilia, and acute eosinophilic leukemia. Several transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Apr 2011]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 5-131966431-G-A is Benign according to our data. Variant chr5-131966431-G-A is described in ClinVar as [Benign]. Clinvar id is 3039632.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-131966431-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.24 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACSL6	NM_001009185.3	c.1698C>T	p.Ile566=	synonymous_variant	17/21	ENST00000651883.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACSL6	ENST00000651883.2	c.1698C>T	p.Ile566=	synonymous_variant	17/21		NM_001009185.3	A1
	ENST00000446275.1	n.301-1528G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00179 AC: 273 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00620

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000517 AC: 130 AN: 251272 Hom.: 0 AF XY: 0.000353 AC XY: 48 AN XY: 135786

Gnomad AFR exome AF: 0.00714

Gnomad AMR exome AF: 0.000376

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: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000192 AC: 281 AN: 1461848 Hom.: 1 Cov.: 31 AF XY: 0.000153 AC XY: 111 AN XY: 727226

Gnomad4 AFR exome AF: 0.00654

Gnomad4 AMR exome AF: 0.000425

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.000381

GnomAD4 genome AF: 0.00178 AC: 271 AN: 152270 Hom.: 0 Cov.: 32 AF XY: 0.00184 AC XY: 137 AN XY: 74450

Gnomad4 AFR AF: 0.00614

Gnomad4 AMR AF: 0.000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00103 Hom.: 0

Bravo AF: 0.00211

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

ACSL6-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 28, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
Cadd	Benign	3.6
Dann	Benign	0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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

Other links and lift over

dbSNP: rs73264077; hg19: chr5-131302124; COSMIC: COSV99734885;