NM_001243279.3:c.-23T>C

Variant names:

• chr16-89098761-T-C
• rs189625890
• NM_001243279.3:c.-23T>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS2_Supporting

The NM_001243279.3(ACSF3):​c.-23T>C variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0027 in 454,162 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0024 (1 hom., cov: 34)
  • Exomes 𝑓: 0.0029 (4 hom.)
• Consequence: ACSF3 NM_001243279.3 splice_region
• Scores: Splicing: ADA: 0.00003359
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0130
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BS2: High Homozygotes in GnomAdExome4 at 4 AR,AD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.-23T>C		splice_region	Exon 2 of 11	NP_001230208.1	Q4G176
	ACSF3	NM_001243279.3	MANE Select	c.-23T>C		5_prime_UTR	Exon 2 of 11	NP_001230208.1	Q4G176
	ACSF3	NM_174917.5		c.-23T>C		splice_region	Exon 2 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.-23T>C		splice_region	Exon 2 of 11	ENSP00000479130.1	Q4G176
	ACSF3	ENST00000614302.5	TSL:5 MANE Select	c.-23T>C		5_prime_UTR	Exon 2 of 11	ENSP00000479130.1	Q4G176
	ACSF3	ENST00000378345.8	TSL:1	c.-129-3843T>C		intron	N/A	ENSP00000367596.4	F5H5A1

Frequencies

GnomAD3 genomes AF: 0.00238 AC: 363 AN: 152240 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00406

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00205 AC: 267 AN: 130506 AF XY: 0.00195

Gnomad AFR exome AF: 0.000822

Gnomad AMR exome AF: 0.00103

Gnomad ASJ exome AF: 0.00432

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00130

Gnomad NFE exome AF: 0.00374

Gnomad OTH exome AF: 0.00225

GnomAD4 exome AF: 0.00286 AC: 862 AN: 301804 Hom.: 4 Cov.: 0 AF XY: 0.00265 AC XY: 455 AN XY: 172002

African (AFR) AF: 0.000585 AC: 5 AN: 8554

American (AMR) AF: 0.000843 AC: 23 AN: 27274

Ashkenazi Jewish (ASJ) AF: 0.00426 AC: 46 AN: 10786

East Asian (EAS) AF: 0.00 AC: 0 AN: 9210

South Asian (SAS) AF: 0.0000335 AC: 2 AN: 59650

European-Finnish (FIN) AF: 0.00113 AC: 14 AN: 12374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1150

European-Non Finnish (NFE) AF: 0.00460 AC: 731 AN: 158762

Other (OTH) AF: 0.00292 AC: 41 AN: 14044

GnomAD4 genome AF: 0.00238 AC: 363 AN: 152358 Hom.: 1 Cov.: 34 AF XY: 0.00199 AC XY: 148 AN XY: 74510

African (AFR) AF: 0.000601 AC: 25 AN: 41588

American (AMR) AF: 0.00144 AC: 22 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00374 AC: 13 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.000659 AC: 7 AN: 10624

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00406 AC: 276 AN: 68026

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00312 Hom.: 0

Bravo AF: 0.00260

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.43
DANN	Benign	0.75
PhyloP100		-0.013
Mutation Taster		=300/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000034
dbscSNV1_RF	Benign	0.0
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: rs189625890; hg19: chr16-89165169;