16-89100533-C-T

Variant names:

• chr16-89100533-C-T
• rs7195892
• NM_001243279.3:c.-20-129C>T

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.-20-129C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.69 in 892,160 control chromosomes in the GnomAD database, including 216,453 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.72 (39703 hom., cov: 33)
  • Exomes 𝑓: 0.68 (176750 hom.)
• Consequence: ACSF3 NM_001243279.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.73
• Publications: 3 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=-0.92).
• BP6: Variant 16-89100533-C-T is Benign according to our data. Variant chr16-89100533-C-T is described in ClinVar as Benign. ClinVar VariationId is 1188936.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.779 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.-20-129C>T		intron	N/A	NP_001230208.1	Q4G176
	ACSF3	NM_001127214.4		c.-20-129C>T		intron	N/A	NP_001120686.1	Q4G176
	ACSF3	NM_174917.5		c.-20-129C>T		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.-20-129C>T		intron	N/A	ENSP00000479130.1	Q4G176
	ACSF3	ENST00000378345.8	TSL:1	c.-129-2071C>T		intron	N/A	ENSP00000367596.4	F5H5A1
	ACSF3	ENST00000871968.1		c.-20-129C>T		intron	N/A	ENSP00000542027.1

Frequencies

GnomAD3 genomes AF: 0.716 AC: 108906 AN: 152018 Hom.: 39682 Cov.: 33

Gnomad AFR AF: 0.623

Gnomad AMI AF: 0.762

Gnomad AMR AF: 0.782

Gnomad ASJ AF: 0.714

Gnomad EAS AF: 0.445

Gnomad SAS AF: 0.547

Gnomad FIN AF: 0.753

Gnomad MID AF: 0.726

Gnomad NFE AF: 0.785

Gnomad OTH AF: 0.729

GnomAD4 exome AF: 0.685 AC: 506887 AN: 740024 Hom.: 176750 AF XY: 0.682 AC XY: 256652 AN XY: 376336

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.555 AC: 11029 AN: 19878

American (AMR) AF: 0.764 AC: 16436 AN: 21516

Ashkenazi Jewish (ASJ) AF: 0.680 AC: 11267 AN: 16578

East Asian (EAS) AF: 0.462 AC: 15421 AN: 33376

South Asian (SAS) AF: 0.510 AC: 28946 AN: 56732

European-Finnish (FIN) AF: 0.761 AC: 22916 AN: 30108

Middle Eastern (MID) AF: 0.680 AC: 1812 AN: 2664

European-Non Finnish (NFE) AF: 0.716 AC: 374167 AN: 522644

Other (OTH) AF: 0.681 AC: 24893 AN: 36528

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.716 AC: 108969 AN: 152136 Hom.: 39703 Cov.: 33 AF XY: 0.711 AC XY: 52915 AN XY: 74382

African (AFR) AF: 0.622 AC: 25808 AN: 41482

American (AMR) AF: 0.782 AC: 11974 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.714 AC: 2477 AN: 3470

East Asian (EAS) AF: 0.445 AC: 2301 AN: 5166

South Asian (SAS) AF: 0.548 AC: 2641 AN: 4822

European-Finnish (FIN) AF: 0.753 AC: 7970 AN: 10588

Middle Eastern (MID) AF: 0.716 AC: 209 AN: 292

European-Non Finnish (NFE) AF: 0.785 AC: 53357 AN: 67988

Other (OTH) AF: 0.728 AC: 1537 AN: 2112

Alfa AF: 0.748 Hom.: 5542

Bravo AF: 0.717

Asia WGS AF: 0.546 AC: 1898 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.093
DANN	Benign	0.55
PhyloP100		-2.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs7195892; hg19: chr16-89166941; COSMIC: COSV107361726; COSMIC: COSV107361726;