12-81078185-C-G

Variant names:

• chr12-81078185-C-G
• rs575214916
• NM_024560.4:c.65C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_024560.4(ACSS3):​c.65C>G​(p.Pro22Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,546,602 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P22H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: ACSS3 NM_024560.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.34
• Publications: 0 publications found

Genes affected

ACSS3 (HGNC:24723): (acyl-CoA synthetase short chain family member 3) Enables propionate-CoA ligase activity. Predicted to be involved in ketone body biosynthetic process. Located in mitochondrial matrix. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.066940844).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024560.4. 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
	ACSS3	NM_024560.4	MANE Select	c.65C>G	p.Pro22Arg	missense	Exon 1 of 16	NP_078836.1	Q9H6R3-1
	ACSS3	NM_001330242.2		c.65C>G	p.Pro22Arg	missense	Exon 1 of 16	NP_001317171.1	A0A0B4J1R2
	ACSS3	NM_001330243.2		c.-941C>G		5_prime_UTR	Exon 1 of 17	NP_001317172.1	Q9H6R3-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACSS3	ENST00000548058.6	TSL:1 MANE Select	c.65C>G	p.Pro22Arg	missense	Exon 1 of 16	ENSP00000449535.1	Q9H6R3-1
	ACSS3	ENST00000261206.7	TSL:1	c.65C>G	p.Pro22Arg	missense	Exon 1 of 16	ENSP00000261206.3	A0A0B4J1R2
	ACSS3	ENST00000965760.1		c.65C>G	p.Pro22Arg	missense	Exon 1 of 16	ENSP00000635819.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152096 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000588 AC: 9 AN: 153186 AF XY: 0.0000820

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000143 AC: 20 AN: 1394388 Hom.: 0 Cov.: 31 AF XY: 0.0000217 AC XY: 15 AN XY: 689770

African (AFR) AF: 0.00 AC: 0 AN: 30684

American (AMR) AF: 0.00 AC: 0 AN: 30490

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24220

East Asian (EAS) AF: 0.00 AC: 0 AN: 36602

South Asian (SAS) AF: 0.000222 AC: 18 AN: 80958

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46088

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5380

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1082470

Other (OTH) AF: 0.0000348 AC: 2 AN: 57496

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152214 Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1 AN XY: 74398

African (AFR) AF: 0.00 AC: 0 AN: 41562

American (AMR) AF: 0.00 AC: 0 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67998

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000434 Hom.: 0

ExAC AF: 0.0000516 AC: 6

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.067	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.3
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.030
Sift	Benign	0.038	D
Sift4G	Uncertain	0.057	T
Polyphen		0.24	B
Vest4		0.33
MutPred		0.38		Gain of MoRF binding (P = 0.0025)
MVP		0.16
MPC		0.79
ClinPred		0.14	T
GERP RS		3.7
PromoterAI		-0.11	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.063
gMVP		0.56
Mutation Taster		=97/3	polymorphism

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: rs575214916; hg19: chr12-81471964;