rs377217672

Variant names:

• chr16-89114333-G-A
• rs377217672
• NM_001243279.3:c.978-6G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-89114333-G-A
• chr16-89114333-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_001243279.3(ACSF3):​c.978-6G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000582 in 1,613,914 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: ACSF3 NM_001243279.3 splice_region, intron
• Scores: Splicing: ADA: 0.00009440
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0280
• 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)

ENSG00000261546 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 16-89114333-G-A is Benign according to our data. Variant chr16-89114333-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 390065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.978-6G>A		splice_region intron	N/A	NP_001230208.1	Q4G176
	ACSF3	NM_001127214.4		c.978-6G>A		splice_region intron	N/A	NP_001120686.1	Q4G176
	ACSF3	NM_174917.5		c.978-6G>A		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.978-6G>A		splice_region intron	N/A	ENSP00000479130.1	Q4G176
	ACSF3	ENST00000378345.8	TSL:1	c.183-6G>A		splice_region intron	N/A	ENSP00000367596.4	F5H5A1
	ACSF3	ENST00000871968.1		c.978-6G>A		splice_region intron	N/A	ENSP00000542027.1

Frequencies

GnomAD3 genomes AF: 0.000256 AC: 39 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000844

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000120 AC: 30 AN: 250972 AF XY: 0.000125

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000529

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000376 AC: 55 AN: 1461600 Hom.: 0 Cov.: 39 AF XY: 0.0000303 AC XY: 22 AN XY: 727106

African (AFR) AF: 0.00105 AC: 35 AN: 33478

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53150

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111994

Other (OTH) AF: 0.0000497 AC: 3 AN: 60392

GnomAD4 genome AF: 0.000256 AC: 39 AN: 152314 Hom.: 0 Cov.: 33 AF XY: 0.000336 AC XY: 25 AN XY: 74466

African (AFR) AF: 0.000842 AC: 35 AN: 41570

American (AMR) AF: 0.0000653 AC: 1 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68028

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000155 Hom.: 0

Bravo AF: 0.000370

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	1.3
DANN	Benign	0.87
PhyloP100		-0.028
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000094
dbscSNV1_RF	Benign	0.0020
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: rs377217672; hg19: chr16-89180741;