chr16-89098586-G-C

Variant names:

• chr16-89098586-G-C
• rs144570053
• NM_001243279.3:c.-193-5G>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001243279.3(ACSF3):​c.-193-5G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00519 in 450,868 control chromosomes in the GnomAD database, including 15 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0048 (6 hom., cov: 34)
  • Exomes 𝑓: 0.0054 (9 hom.)
• Consequence: ACSF3 NM_001243279.3 splice_region, intron
• Scores: Splicing: ADA: 0.00009940
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.181
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 16-89098586-G-C is Benign according to our data. Variant chr16-89098586-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 380080.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00476 (726/152372) while in subpopulation AMR AF = 0.00757 (116/15314). AF 95% confidence interval is 0.00646. There are 6 homozygotes in GnomAd4. There are 364 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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.-193-5G>C		splice_region intron	N/A	NP_001230208.1	Q4G176
	ACSF3	NM_001127214.4		c.-20-2076G>C		intron	N/A	NP_001120686.1	Q4G176
	ACSF3	NM_174917.5		c.-193-5G>C		splice_region intron	N/A	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.-193-5G>C		splice_region intron	N/A	ENSP00000479130.1	Q4G176
	ACSF3	ENST00000378345.8	TSL:1	c.-129-4018G>C		intron	N/A	ENSP00000367596.4	F5H5A1
	ACSF3	ENST00000871968.1		c.-193-5G>C		splice_region intron	N/A	ENSP00000542027.1

Frequencies

GnomAD3 genomes AF: 0.00477 AC: 726 AN: 152254 Hom.: 6 Cov.: 34

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00758

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00442

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00676

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.00540 AC: 696 AN: 128956 AF XY: 0.00512

Gnomad AFR exome AF: 0.00164

Gnomad AMR exome AF: 0.00645

Gnomad ASJ exome AF: 0.0126

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00510

Gnomad NFE exome AF: 0.00783

Gnomad OTH exome AF: 0.00452

GnomAD4 exome AF: 0.00541 AC: 1615 AN: 298496 Hom.: 9 Cov.: 0 AF XY: 0.00520 AC XY: 882 AN XY: 169688

African (AFR) AF: 0.00141 AC: 12 AN: 8484

American (AMR) AF: 0.00650 AC: 177 AN: 27236

Ashkenazi Jewish (ASJ) AF: 0.0119 AC: 127 AN: 10708

East Asian (EAS) AF: 0.00 AC: 0 AN: 9120

South Asian (SAS) AF: 0.000252 AC: 15 AN: 59554

European-Finnish (FIN) AF: 0.00675 AC: 83 AN: 12296

Middle Eastern (MID) AF: 0.00262 AC: 3 AN: 1146

European-Non Finnish (NFE) AF: 0.00720 AC: 1124 AN: 156014

Other (OTH) AF: 0.00531 AC: 74 AN: 13938

GnomAD4 genome AF: 0.00476 AC: 726 AN: 152372 Hom.: 6 Cov.: 34 AF XY: 0.00488 AC XY: 364 AN XY: 74520

African (AFR) AF: 0.00101 AC: 42 AN: 41586

American (AMR) AF: 0.00757 AC: 116 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 36 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

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

European-Finnish (FIN) AF: 0.00442 AC: 47 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00676 AC: 460 AN: 68036

Other (OTH) AF: 0.0109 AC: 23 AN: 2116

Alfa AF: 0.00560 Hom.: 1

Bravo AF: 0.00505

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

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	-0.83
CADD	Benign	1.0
DANN	Benign	0.42
PhyloP100		0.18
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=59/41	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000099
dbscSNV1_RF	Benign	0.044
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: rs144570053; hg19: chr16-89164994;