rs144681140

Variant names:

• chr16-89145306-G-A
• rs144681140
• NM_001243279.3:c.1406G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-89145306-G-A
• chr16-89145306-G-C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

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. 15/22 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:4
• Conservation: PhyloP100: 1.44
• Publications: 13 publications found

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, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_001243279.3
• 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 VariationId is 203601.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 38 AR,AD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACSF3	NM_001243279.3	MANE Select	c.1406G>A	p.Arg469Gln	missense	Exon 9 of 11	NP_001230208.1	Q4G176
	ACSF3	NM_001127214.4		c.1406G>A	p.Arg469Gln	missense	Exon 8 of 10	NP_001120686.1	Q4G176
	ACSF3	NM_174917.5		c.1406G>A	p.Arg469Gln	missense	Exon 9 of 11	NP_777577.2	Q4G176

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACSF3	ENST00000614302.5	TSL:5 MANE Select	c.1406G>A	p.Arg469Gln	missense	Exon 9 of 11	ENSP00000479130.1	Q4G176
	ACSF3	ENST00000378345.8	TSL:1	c.611G>A	p.Arg204Gln	missense	Exon 7 of 9	ENSP00000367596.4	F5H5A1
	ACSF3	ENST00000871968.1		c.1454G>A	p.Arg485Gln	missense	Exon 10 of 12	ENSP00000542027.1

Frequencies

GnomAD3 genomes AF: 0.00467 AC: 711 AN: 152168 Hom.: 1 Cov.: 33

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

GnomAD2 exomes AF: 0.00431 AC: 1084 AN: 251230 AF XY: 0.00436

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 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.: 38 Cov.: 32 AF XY: 0.00637 AC XY: 4635 AN XY: 727192

African (AFR) AF: 0.00122 AC: 41 AN: 33480

American (AMR) AF: 0.00179 AC: 80 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.000650 AC: 17 AN: 26136

East Asian (EAS) AF: 0.000982 AC: 39 AN: 39700

South Asian (SAS) AF: 0.00369 AC: 318 AN: 86256

European-Finnish (FIN) AF: 0.00416 AC: 222 AN: 53418

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5768

European-Non Finnish (NFE) AF: 0.00763 AC: 8482 AN: 1111930

Other (OTH) AF: 0.00444 AC: 268 AN: 60394

GnomAD4 genome AF: 0.00467 AC: 711 AN: 152286 Hom.: 1 Cov.: 33 AF XY: 0.00443 AC XY: 330 AN XY: 74456

African (AFR) AF: 0.00137 AC: 57 AN: 41564

American (AMR) AF: 0.00334 AC: 51 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5182

South Asian (SAS) AF: 0.00394 AC: 19 AN: 4824

European-Finnish (FIN) AF: 0.00433 AC: 46 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00776 AC: 528 AN: 68016

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00617 Hom.: 6

Bravo AF: 0.00416

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00623 AC: 24

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00779 AC: 67

ExAC AF: 0.00458 AC: 556

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00654

EpiControl AF: 0.00575

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	1	Combined malonic and methylmalonic acidemia (4)
-	1	1	not provided (2)
-	-	1	ACSF3-related disorder (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.042	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.70	N
PhyloP100		1.4
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.11
Sift	Uncertain	0.025	D
Sift4G	Benign	0.089	T
Polyphen		0.011	B
Vest4		0.53
MVP		0.26
MPC		0.059
ClinPred		0.017	T
GERP RS		3.6
Varity_R		0.093
gMVP		0.49
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs144681140; hg19: chr16-89211714;