chr16-89114475-G-A

Variant names:

• chr16-89114475-G-A
• rs3743979
• NM_001243279.3:c.1114G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V372L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.71 (38474 hom., cov: 32)
  • Exomes 𝑓: 0.74 (398474 hom.)
• Consequence: ACSF3 NM_001243279.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.533
• Publications: 34 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)

ENSG00000261546 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 991087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.752 is higher than 0.05.

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.1114G>A	p.Val372Met	missense	Exon 6 of 11	NP_001230208.1	Q4G176
	ACSF3	NM_001127214.4		c.1114G>A	p.Val372Met	missense	Exon 5 of 10	NP_001120686.1	Q4G176
	ACSF3	NM_174917.5		c.1114G>A	p.Val372Met	missense	Exon 6 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.1114G>A	p.Val372Met	missense	Exon 6 of 11	ENSP00000479130.1	Q4G176
	ACSF3	ENST00000378345.8	TSL:1	c.319G>A	p.Val107Met	missense	Exon 4 of 9	ENSP00000367596.4	F5H5A1
	ACSF3	ENST00000871968.1		c.1114G>A	p.Val372Met	missense	Exon 6 of 12	ENSP00000542027.1

Frequencies

GnomAD3 genomes AF: 0.707 AC: 107453 AN: 151950 Hom.: 38462 Cov.: 32

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

GnomAD2 exomes AF: 0.716 AC: 178900 AN: 249890 AF XY: 0.712

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 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.: 79 AF XY: 0.733 AC XY: 532654 AN XY: 726510

African (AFR) AF: 0.627 AC: 21004 AN: 33476

American (AMR) AF: 0.796 AC: 35591 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.747 AC: 19529 AN: 26134

East Asian (EAS) AF: 0.497 AC: 19714 AN: 39700

South Asian (SAS) AF: 0.605 AC: 52204 AN: 86254

European-Finnish (FIN) AF: 0.778 AC: 40268 AN: 51738

Middle Eastern (MID) AF: 0.755 AC: 4344 AN: 5756

European-Non Finnish (NFE) AF: 0.754 AC: 838652 AN: 1111964

Other (OTH) AF: 0.716 AC: 43225 AN: 60376

GnomAD4 genome AF: 0.707 AC: 107494 AN: 152068 Hom.: 38474 Cov.: 32 AF XY: 0.705 AC XY: 52435 AN XY: 74326

African (AFR) AF: 0.624 AC: 25859 AN: 41460

American (AMR) AF: 0.761 AC: 11635 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.744 AC: 2580 AN: 3470

East Asian (EAS) AF: 0.471 AC: 2426 AN: 5150

South Asian (SAS) AF: 0.588 AC: 2827 AN: 4808

European-Finnish (FIN) AF: 0.778 AC: 8246 AN: 10600

Middle Eastern (MID) AF: 0.786 AC: 231 AN: 294

European-Non Finnish (NFE) AF: 0.757 AC: 51485 AN: 67974

Other (OTH) AF: 0.726 AC: 1534 AN: 2114

Alfa AF: 0.738 Hom.: 193608

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Combined malonic and methylmalonic acidemia (2)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Methylmalonic acidemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	8.1
DANN	Benign	0.94
DEOGEN2	Benign	0.048	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.15	T
MetaRNN	Benign	0.0000025	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.53
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.037
Sift	Benign	0.10	T
Sift4G	Benign	0.11	T
Polyphen		0.022	B
Vest4		0.070
MPC		0.18
ClinPred		0.011	T
GERP RS		-0.27
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.074
gMVP		0.42
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3743979; hg19: chr16-89180883; COSMIC: COSV58077067; COSMIC: COSV58077067;