rs144681140

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001243279.3(ACSF3):c.1406G>A(p.Arg469Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00631 in 1,614,082 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R469R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0047 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0065 ( 38 hom. )

Consequence

ACSF3
NM_001243279.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:4

Conservation

PhyloP100: 1.44

Variant links:

Genes affected

ACSF3 (HGNC:27288): (acyl-CoA synthetase family member 3) This gene encodes a member of the acyl-CoA synthetase family of enzymes that activate fatty acids by catalyzing the formation of a thioester linkage between fatty acids and coenzyme A. The encoded protein is localized to mitochondria, has high specificity for malonate and methylmalonate and possesses malonyl-CoA synthetase activity. Mutations in this gene are a cause of combined malonic and methylmalonic aciduria. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Sep 2013]

ACSF3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.016626418).

BP6

Variant 16-89145306-G-A is Benign according to our data. Variant chr16-89145306-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 203601.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=3, Likely_benign=3}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00467 (711/152286) while in subpopulation NFE AF= 0.00776 (528/68016). AF 95% confidence interval is 0.00722. There are 1 homozygotes in gnomad4. There are 330 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACSF3	NM_001243279.3 linkuse as main transcript	c.1406G>A	p.Arg469Gln	missense_variant	9/11	ENST00000614302.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACSF3	ENST00000614302.5 linkuse as main transcript	c.1406G>A	p.Arg469Gln	missense_variant	9/11	5	NM_001243279.3	P1

Frequencies

GnomAD3 genomes

AF:

0.00467

AC:

711

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00138

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00334

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.00394

Gnomad FIN

AF:

0.00433

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00776

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00431

AC:

1084

AN:

251230

Hom.:

AF XY:

0.00436

AC XY:

592

AN XY:

135828

show subpopulations

Gnomad AFR exome

AF:

0.00111

Gnomad AMR exome

AF:

0.00185

Gnomad ASJ exome

AF:

0.000596

Gnomad EAS exome

AF:

0.000653

Gnomad SAS exome

AF:

0.00274

Gnomad FIN exome

AF:

0.00370

Gnomad NFE exome

AF:

0.00701

Gnomad OTH exome

AF:

0.00392

GnomAD4 exome

AF:

0.00648

AC:

9476

AN:

1461796

Hom.:

Cov.:

AF XY:

0.00637

AC XY:

4635

AN XY:

727192

show subpopulations

Gnomad4 AFR exome

AF:

0.00122

Gnomad4 AMR exome

AF:

0.00179

Gnomad4 ASJ exome

AF:

0.000650

Gnomad4 EAS exome

AF:

0.000982

Gnomad4 SAS exome

AF:

0.00369

Gnomad4 FIN exome

AF:

0.00416

Gnomad4 NFE exome

AF:

0.00763

Gnomad4 OTH exome

AF:

0.00444

GnomAD4 genome

AF:

0.00467

AC:

711

AN:

152286

Hom.:

Cov.:

AF XY:

0.00443

AC XY:

330

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.00137

Gnomad4 AMR

AF:

0.00334

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.00394

Gnomad4 FIN

AF:

0.00433

Gnomad4 NFE

AF:

0.00776

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00660

Hom.:

Bravo

AF:

0.00416

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00623

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.00779

AC:

ExAC

AF:

0.00458

AC:

556

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00654

EpiControl

AF:

0.00575

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Combined malonic and methylmalonic acidemia

Uncertain:3Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	May 01, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 26, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	The ACSF3 c.1406G>A; p.Arg469Gln variant (rs144681140), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 203601). This variant is found in the general population with an overall allele frequency of 0.45% (1271/282590 alleles, including 3 homozygotes) in the Genome Aggregation Database. The arginine at codon 469 is weakly conserved, and computational analyses predict that this variant is neutral (REVEL: 0.114). While the high population frequency suggests that this is likely a benign variant, given the lack of clinical and functional data, the significance of this variant is uncertain at this time. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 17, 2017

The R469Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to ourknowledge. The R469Q variant is observed in 425/66442 (0.64%) alleles from individuals of European backgroundincluding one homozygote (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). TheR469Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as theseresidues differ in some properties. This substitution occurs at a position that is not conserved. In silico analysis isinconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Insummary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or arare benign variant. -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 21, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

ACSF3-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 19, 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). -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2023

ACSF3: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.43

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.042

T;T;T;T;.

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.17

FATHMM_MKL

Benign

0.72

M_CAP

Benign

0.014

MetaRNN

Benign

0.017

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.70

N;N;N;.;.

MutationTaster

Benign

0.98

N;N;N

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.43

N;.;N;N;N

REVEL

Benign

0.11

Sift

Uncertain

0.025

D;.;D;D;D

Sift4G

Benign

0.089

T;T;T;T;T

Polyphen

0.011

B;B;B;.;.

Vest4

0.53

MVP

0.26

MPC

0.059

ClinPred

0.017

GERP RS

3.6

Varity_R

0.093

gMVP

0.49

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

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