16-89093921-C-G

Variant names:

• chr16-89093921-C-G
• rs145228567
• NM_001243279.3:c.-269C>G

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.-269C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.163 in 324,882 control chromosomes in the GnomAD database, including 6,453 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (2007 hom., cov: 32)
  • Exomes 𝑓: 0.19 (4446 hom.)
• Consequence: ACSF3 NM_001243279.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.368
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 16-89093921-C-G is Benign according to our data. Variant chr16-89093921-C-G is described in ClinVar as Benign. ClinVar VariationId is 1248015.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.309 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.-269C>G		5_prime_UTR	Exon 1 of 11	NP_001230208.1	Q4G176
	ACSF3	NM_001127214.4		c.-96C>G		5_prime_UTR	Exon 1 of 10	NP_001120686.1	Q4G176
	ACSF3	NM_174917.5		c.-265C>G		5_prime_UTR	Exon 1 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.-269C>G		5_prime_UTR	Exon 1 of 11	ENSP00000479130.1	Q4G176
	ACSF3	ENST00000378345.8	TSL:1	c.-201C>G		5_prime_UTR	Exon 1 of 9	ENSP00000367596.4	F5H5A1
	ACSF3	ENST00000871968.1		c.-269C>G		5_prime_UTR	Exon 1 of 12	ENSP00000542027.1

Frequencies

GnomAD3 genomes AF: 0.136 AC: 20282 AN: 149184 Hom.: 1992 Cov.: 32

Gnomad AFR AF: 0.0334

Gnomad AMI AF: 0.0691

Gnomad AMR AF: 0.316

Gnomad ASJ AF: 0.120

Gnomad EAS AF: 0.192

Gnomad SAS AF: 0.203

Gnomad FIN AF: 0.114

Gnomad MID AF: 0.0796

Gnomad NFE AF: 0.155

Gnomad OTH AF: 0.135

GnomAD2 exomes AF: 0.228 AC: 16471 AN: 72360 AF XY: 0.211

Gnomad AFR exome AF: 0.0317

Gnomad AMR exome AF: 0.509

Gnomad ASJ exome AF: 0.130

Gnomad EAS exome AF: 0.220

Gnomad FIN exome AF: 0.104

Gnomad NFE exome AF: 0.151

Gnomad OTH exome AF: 0.170

GnomAD4 exome AF: 0.186 AC: 32674 AN: 175590 Hom.: 4446 Cov.: 0 AF XY: 0.182 AC XY: 19557 AN XY: 107464

African (AFR) AF: 0.0418 AC: 152 AN: 3638

American (AMR) AF: 0.496 AC: 7909 AN: 15958

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 936 AN: 7558

East Asian (EAS) AF: 0.217 AC: 268 AN: 1236

South Asian (SAS) AF: 0.194 AC: 8142 AN: 41960

European-Finnish (FIN) AF: 0.101 AC: 844 AN: 8358

Middle Eastern (MID) AF: 0.0831 AC: 59 AN: 710

European-Non Finnish (NFE) AF: 0.149 AC: 13285 AN: 88900

Other (OTH) AF: 0.148 AC: 1079 AN: 7272

GnomAD4 genome AF: 0.136 AC: 20305 AN: 149292 Hom.: 2007 Cov.: 32 AF XY: 0.139 AC XY: 10095 AN XY: 72796

African (AFR) AF: 0.0333 AC: 1377 AN: 41294

American (AMR) AF: 0.317 AC: 4764 AN: 15036

Ashkenazi Jewish (ASJ) AF: 0.120 AC: 409 AN: 3416

East Asian (EAS) AF: 0.193 AC: 990 AN: 5142

South Asian (SAS) AF: 0.202 AC: 974 AN: 4826

European-Finnish (FIN) AF: 0.114 AC: 1092 AN: 9584

Middle Eastern (MID) AF: 0.0788 AC: 23 AN: 292

European-Non Finnish (NFE) AF: 0.155 AC: 10325 AN: 66712

Other (OTH) AF: 0.139 AC: 288 AN: 2078

Alfa AF: 0.0665 Hom.: 86

Bravo AF: 0.150

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	10
DANN	Benign	0.36
PhyloP100		0.37
PromoterAI		0.22	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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: rs145228567; hg19: chr16-89160329; COSMIC: COSV104615700; COSMIC: COSV104615700;