16-20637447-A-G

Position:

• chr16-20637447-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001318890.3(ACSM1):​c.1121T>C​(p.Leu374Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,460 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: ACSM1 NM_001318890.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.624

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32643396).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACSM1	NM_001318890.3	c.1121T>C	p.Leu374Pro	missense_variant	9/14	ENST00000520010.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACSM1	ENST00000520010.6	c.1121T>C	p.Leu374Pro	missense_variant	9/14	1	NM_001318890.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461460 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727052

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.11	T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.067	N
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.33	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-4.5	D;D
REVEL	Benign	0.26
Sift	Uncertain	0.017	D;D
Sift4G	Uncertain	0.026	D;D
Polyphen		0.0020	B;B
Vest4		0.28
MutPred		0.77		Loss of catalytic residue at L374 (P = 0.0149);Loss of catalytic residue at L374 (P = 0.0149);
MVP		0.26
MPC		0.15
ClinPred		0.33	T
GERP RS		0.044
Varity_R		0.62
gMVP		0.62

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

Publications

LitVar

Other links and lift over

dbSNP: rs1233553650; hg19: chr16-20648769; COSMIC: COSV54637914;