16-20636755-A-G

Variant names:

• chr16-20636755-A-G
• NM_001318890.3:c.1283T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001318890.3(ACSM1):​c.1283T>C​(p.Leu428Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACSM1 NM_001318890.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.08

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACSM1	NM_001318890.3	c.1283T>C	p.Leu428Pro	missense_variant	Exon 10 of 14	ENST00000520010.6	NP_001305819.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACSM1	ENST00000520010.6	c.1283T>C	p.Leu428Pro	missense_variant	Exon 10 of 14	1	NM_001318890.3	ENSP00000428047.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 18, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1283T>C (p.L428P) alteration is located in exon 9 (coding exon 9) of the ACSM1 gene. This alteration results from a T to C substitution at nucleotide position 1283, causing the leucine (L) at amino acid position 428 to be replaced by a proline (P). 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	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T;T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.31	.;T
M_CAP	Benign	0.030	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Benign	-0.45	T
MutationAssessor	Pathogenic	3.7	H;H
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-5.4	D;D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;D
Vest4		0.91
MutPred		0.89		Gain of disorder (P = 0.0155);Gain of disorder (P = 0.0155);
MVP		0.70
MPC		0.54
ClinPred		0.94	D
GERP RS		4.6
Varity_R		0.68
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-20648077;