rs140986055

Positions:

chr16-89102665-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5

The NM_001284316.2(ACSF3):c.-68C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000477 in 1,613,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

ACSF3
NM_001284316.2 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:2

Conservation

PhyloP100: 7.29

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:

ACSF3 (HGNC:):

ACSF3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.799

PP5

Variant 16-89102665-C-T is Pathogenic according to our data. Variant chr16-89102665-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 31140.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACSF3	NM_001243279.3 linkuse as main transcript	c.728C>T	p.Pro243Leu	missense_variant	4/11	ENST00000614302.5	NP_001230208.1	Q4G176

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACSF3	ENST00000614302.5 linkuse as main transcript	c.728C>T	p.Pro243Leu	missense_variant	4/11	5	NM_001243279.3	ENSP00000479130.1		Q4G176

Frequencies

GnomAD3 genomes

AF:

0.000217

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000677

AC:

AN:

251160

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135800

show subpopulations

Gnomad AFR exome

AF:

0.000862

Gnomad AMR exome

AF:

0.0000289

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000301

AC:

AN:

1461606

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

727124

show subpopulations

Gnomad4 AFR exome

AF:

0.000807

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000989

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.000217

AC:

AN:

152292

Hom.:

Cov.:

AF XY:

0.000255

AC XY:

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.000722

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000487

Hom.:

Bravo

AF:

0.000264

ESP6500AA

AF:

0.000910

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Combined malonic and methylmalonic acidemia

Pathogenic:2Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 19, 2021	This sequence change replaces proline with leucine at codon 243 of the ACSF3 protein (p.Pro243Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs140986055, ExAC 0.1%). This missense change has been observed in individual(s) with combined malonic and methylmalonic aciduria (PMID: 21841779). ClinVar contains an entry for this variant (Variation ID: 31140). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 14, 2011	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Mar 20, 2024	PS3_Moderate, PM1, PM3_supporting, PP3 -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 25, 2023

Variant summary: ACSF3 c.728C>T (p.Pro243Leu) results in a non-conservative amino acid change located in the AMP-dependent synthetase/ligase domain (IPR000873) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 251160 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ACSF3 causing Combined Malonic And Methylmalonic Aciduria (6.8e-05 vs 0.0058), allowing no conclusion about variant significance. c.728C>T has been reported in the literature as a homozygous genotype in at-least one individual affected with biochemical features Combined Malonic And Methylmalonic Aciduria (example, PMID: 30740739, 21841779). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.75

BayesDel_addAF

Uncertain

0.075

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.44

T;T;T;D

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.98

.;D;.;D

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.80

D;D;D;D

MetaSVM

Uncertain

0.66

MutationAssessor

Pathogenic

3.9

H;H;H;.

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-9.7

D;.;D;D

REVEL

Uncertain

0.62

Sift

Pathogenic

0.0

D;.;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;D;D;.

Vest4

0.88

MVP

0.65

MPC

0.31

ClinPred

1.0

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.96

gMVP

0.87

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