Genetic Variant ACSM1:p.Cys376Tyr (chr16-20637441-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001318890.3(ACSM1):c.1127G>A(p.Cys376Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. C376F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

ACSM1
NM_001318890.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.975

Publications

0 publications found

Variant links:

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]

ACSM1 links:

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]

ACSM3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.857

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACSM1	NM_001318890.3	MANE Select	c.1127G>A	p.Cys376Tyr	missense	Exon 9 of 14	NP_001305819.1	Q08AH1-1
ACSM1	NM_052956.3		c.1127G>A	p.Cys376Tyr	missense	Exon 8 of 13	NP_443188.2	Q08AH1-1
ACSM1	NR_134918.2		n.1132G>A		non_coding_transcript_exon	Exon 8 of 11

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACSM1	ENST00000520010.6	TSL:1 MANE Select	c.1127G>A	p.Cys376Tyr	missense	Exon 9 of 14	ENSP00000428047.1	Q08AH1-1
ACSM1	ENST00000307493.8	TSL:1	c.1127G>A	p.Cys376Tyr	missense	Exon 8 of 13	ENSP00000301956.3	Q08AH1-1
ACSM1	ENST00000519745.5	TSL:1	n.*449G>A		non_coding_transcript_exon	Exon 8 of 11	ENSP00000428650.1	Q08AH1-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251334

AF XY:

0.00000736

show subpopulations

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.12

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.24

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.72

M_CAP

Benign

0.012

MetaRNN

Pathogenic

0.86

MetaSVM

Benign

-0.33

MutationAssessor

Pathogenic

3.3

PhyloP100

0.97

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-9.5

REVEL

Benign

0.29

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.53

MutPred

0.74

Gain of phosphorylation at C376 (P = 0.0879)

MVP

0.53

MPC

0.55

ClinPred

1.0

GERP RS

5.1

Varity_R

0.88

gMVP

0.77

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over