rs3743979

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001243279.3(ACSF3):c.1114G>A(p.Val372Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.733 in 1,612,188 control chromosomes in the GnomAD database, including 436,948 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.71 ( 38474 hom., cov: 32)

Exomes 𝑓: 0.74 ( 398474 hom. )

Consequence

ACSF3
NM_001243279.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.533

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:

(HGNC:):

links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.4674323E-6).

BP6

Variant 16-89114475-G-A is Benign according to our data. Variant chr16-89114475-G-A is described in ClinVar as [Benign]. Clinvar id is 991087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89114475-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.752 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACSF3	NM_001243279.3 linkuse as main transcript	c.1114G>A	p.Val372Met	missense_variant	6/11	ENST00000614302.5	NP_001230208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACSF3	ENST00000614302.5 linkuse as main transcript	c.1114G>A	p.Val372Met	missense_variant	6/11	5	NM_001243279.3	ENSP00000479130	P1
	ENST00000562782.1 linkuse as main transcript	n.805C>T		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes

AF:

0.707

AC:

107453

AN:

151950

Hom.:

38462

Cov.:

show subpopulations

Gnomad AFR

AF:

0.625

Gnomad AMI

AF:

0.736

Gnomad AMR

AF:

0.761

Gnomad ASJ

AF:

0.744

Gnomad EAS

AF:

0.471

Gnomad SAS

AF:

0.587

Gnomad FIN

AF:

0.778

Gnomad MID

AF:

0.791

Gnomad NFE

AF:

0.757

Gnomad OTH

AF:

0.729

GnomAD3 exomes

AF:

0.716

AC:

178900

AN:

249890

Hom.:

65253

AF XY:

0.712

AC XY:

96431

AN XY:

135342

show subpopulations

Gnomad AFR exome

AF:

0.627

Gnomad AMR exome

AF:

0.802

Gnomad ASJ exome

AF:

0.750

Gnomad EAS exome

AF:

0.477

Gnomad SAS exome

AF:

0.603

Gnomad FIN exome

AF:

0.781

Gnomad NFE exome

AF:

0.756

Gnomad OTH exome

AF:

0.727

GnomAD4 exome

AF:

0.736

AC:

1074531

AN:

1460120

Hom.:

398474

Cov.:

AF XY:

0.733

AC XY:

532654

AN XY:

726510

show subpopulations

Gnomad4 AFR exome

AF:

0.627

Gnomad4 AMR exome

AF:

0.796

Gnomad4 ASJ exome

AF:

0.747

Gnomad4 EAS exome

AF:

0.497

Gnomad4 SAS exome

AF:

0.605

Gnomad4 FIN exome

AF:

0.778

Gnomad4 NFE exome

AF:

0.754

Gnomad4 OTH exome

AF:

0.716

GnomAD4 genome

AF:

0.707

AC:

107494

AN:

152068

Hom.:

38474

Cov.:

AF XY:

0.705

AC XY:

52435

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.624

Gnomad4 AMR

AF:

0.761

Gnomad4 ASJ

AF:

0.744

Gnomad4 EAS

AF:

0.471

Gnomad4 SAS

AF:

0.588

Gnomad4 FIN

AF:

0.778

Gnomad4 NFE

AF:

0.757

Gnomad4 OTH

AF:

0.726

Alfa

AF:

0.744

Hom.:

103352

Bravo

AF:

0.703

TwinsUK

AF:

0.755

AC:

2800

ALSPAC

AF:

0.746

AC:

2876

ESP6500AA

AF:

0.624

AC:

2741

ESP6500EA

AF:

0.751

AC:

6462

ExAC

AF:

0.709

AC:

86130

Asia WGS

AF:

0.559

AC:

1944

AN:

3478

EpiCase

AF:

0.761

EpiControl

AF:

0.761

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Combined malonic and methylmalonic acidemia

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Methylmalonic acidemia

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

May 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.50

CADD

Benign

8.1

DANN

Benign

0.94

DEOGEN2

Benign

0.048

T;T;.;T;T;.

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.15

.;T;T;.;T;T

MetaRNN

Benign

0.0000025

T;T;T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.1

L;L;.;L;.;.

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.18

N;.;N;N;N;N

REVEL

Benign

0.037

Sift

Benign

0.10

T;.;T;T;T;T

Sift4G

Benign

0.11

T;T;T;T;T;T

Polyphen

0.022

B;B;.;B;.;.

Vest4

0.070

MPC

0.18

ClinPred

0.011

GERP RS

-0.27

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.074

gMVP

0.42

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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