16-20640534-A-G

Variant names:

• chr16-20640534-A-G
• rs1348555240
• NM_001318890.3:c.1043T>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001318890.3(ACSM1):​c.1043T>C​(p.Leu348Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,836 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ACSM1 NM_001318890.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.59

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACSM1	NM_001318890.3	c.1043T>C	p.Leu348Ser	missense_variant	Exon 8 of 14	ENST00000520010.6	NP_001305819.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACSM1	ENST00000520010.6	c.1043T>C	p.Leu348Ser	missense_variant	Exon 8 of 14	1	NM_001318890.3	ENSP00000428047.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251200 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135748

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461836 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727214

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: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000624 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1043T>C (p.L348S) alteration is located in exon 7 (coding exon 7) of the ACSM1 gene. This alteration results from a T to C substitution at nucleotide position 1043, causing the leucine (L) at amino acid position 348 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0075	T;T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.094	.;T
M_CAP	Benign	0.0080	T
MetaRNN	Uncertain	0.65	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;L
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.29
Sift	Benign	0.097	T;T
Sift4G	Benign	0.16	T;T
Polyphen		0.92	P;P
Vest4		0.57
MutPred		0.54		Loss of catalytic residue at L348 (P = 1e-04);Loss of catalytic residue at L348 (P = 1e-04);
MVP		0.62
MPC		0.49
ClinPred		0.30	T
GERP RS		3.7
Varity_R		0.043
gMVP		0.47

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: rs1348555240; hg19: chr16-20651856;