16-20682268-C-G

Variant names:

• chr16-20682268-C-G
• rs148646745
• NM_001318890.3:c.599G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001318890.3(ACSM1):​c.599G>C​(p.Arg200Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,722 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. R200Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ACSM1 NM_001318890.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.07
• Publications: 2 publications found

Genes affected

ACSM1 (HGNC:18049): (acyl-CoA synthetase medium chain family member 1) Enables CoA-ligase activity. Predicted to be involved in acyl-CoA metabolic process and fatty acid biosynthetic process. Located in mitochondrial matrix. [provided by Alliance of Genome Resources, Apr 2022]

ACSM3 (HGNC:10522): (acyl-CoA synthetase medium chain family member 3) Enables butyrate-CoA ligase activity. Predicted to be involved in acyl-CoA metabolic process and fatty acid biosynthetic process. Located in mitochondrion. Implicated in IgA glomerulonephritis. Biomarker of ulcerative colitis. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30605122).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001318890.3. 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
	ACSM1	NM_001318890.3	MANE Select	c.599G>C	p.Arg200Pro	missense	Exon 4 of 14	NP_001305819.1	Q08AH1-1
	ACSM1	NM_052956.3		c.599G>C	p.Arg200Pro	missense	Exon 3 of 13	NP_443188.2	Q08AH1-1
	ACSM1	NR_134918.2		n.667G>C		non_coding_transcript_exon	Exon 3 of 11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACSM1	ENST00000520010.6	TSL:1 MANE Select	c.599G>C	p.Arg200Pro	missense	Exon 4 of 14	ENSP00000428047.1	Q08AH1-1
	ACSM1	ENST00000307493.8	TSL:1	c.599G>C	p.Arg200Pro	missense	Exon 3 of 13	ENSP00000301956.3	Q08AH1-1
	ACSM1	ENST00000519745.5	TSL:1	n.599G>C		non_coding_transcript_exon	Exon 3 of 11	ENSP00000428650.1	Q08AH1-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460722 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726704

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4960

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111896

Other (OTH) AF: 0.00 AC: 0 AN: 60298

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	14
DANN	Benign	0.71
DEOGEN2	Benign	0.10	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.24	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.8	L
PhyloP100		-2.1
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-3.9	D
REVEL	Benign	0.11
Sift	Benign	0.15	T
Sift4G	Benign	0.23	T
Polyphen		0.90	P
Vest4		0.50
MutPred		0.47		Loss of catalytic residue at R200 (P = 0.0051)
MVP		0.15
MPC		0.46
ClinPred		0.59	D
GERP RS		-7.2
Varity_R		0.50
gMVP		0.83

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: rs148646745; hg19: chr16-20693590;