Genetic Variant ACSF3:p.Val372Leu (chr16-89114475-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001243279.3(ACSF3):c.1114G>T(p.Val372Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V372M) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ACSF3
NM_001243279.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.533

Publications

34 publications found

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 Gene-Disease associations (from GenCC):

combined malonic and methylmalonic acidemia
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

ACSF3 links:

ENSG00000261546 (HGNC:):

ENSG00000261546 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12272009).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001243279.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ACSF3	NM_001243279.3	MANE Select	c.1114G>T	p.Val372Leu	missense	Exon 6 of 11	NP_001230208.1
ACSF3	NM_001127214.4		c.1114G>T	p.Val372Leu	missense	Exon 5 of 10	NP_001120686.1
ACSF3	NM_174917.5		c.1114G>T	p.Val372Leu	missense	Exon 6 of 11	NP_777577.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ACSF3	ENST00000614302.5	TSL:5 MANE Select	c.1114G>T	p.Val372Leu	missense	Exon 6 of 11	ENSP00000479130.1
ACSF3	ENST00000378345.8	TSL:1	c.319G>T	p.Val107Leu	missense	Exon 4 of 9	ENSP00000367596.4
ACSF3	ENST00000317447.9	TSL:2	c.1114G>T	p.Val372Leu	missense	Exon 6 of 11	ENSP00000320646.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

6.85e-7

AC:

AN:

1460192

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726542

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51774

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111988

Other (OTH)

AF:

0.00

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

193608

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.58

CADD

Benign

1.2

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.049

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.34

M_CAP

Benign

0.0083

MetaRNN

Benign

0.12

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.11

PhyloP100

0.53

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.80

REVEL

Benign

0.028

Sift

Benign

0.27

Sift4G

Benign

0.23

Polyphen

0.0010

Vest4

0.15

MutPred

0.35

Loss of glycosylation at T370 (P = 0.1458)

MVP

0.18

MPC

0.065

ClinPred

0.048

GERP RS

-0.27

Varity_R

0.085

gMVP

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over