Genetic Variant ACSM1:p.Lys258Arg (chr16-20669966-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001318890.3(ACSM1):c.773A>G(p.Lys258Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00389 in 1,613,790 control chromosomes in the GnomAD database, including 225 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.021 ( 114 hom., cov: 32)

Exomes 𝑓: 0.0021 ( 111 hom. )

Consequence

ACSM1
NM_001318890.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.626

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0026753545).

BP6

Variant 16-20669966-T-C is Benign according to our data. Variant chr16-20669966-T-C is described in ClinVar as [Benign]. Clinvar id is 786939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0717 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACSM1	NM_001318890.3 link	c.773A>G	p.Lys258Arg	missense_variant	Exon 6 of 14	ENST00000520010.6	NP_001305819.1	Q08AH1-1B2RAP4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACSM1	ENST00000520010.6 link	c.773A>G	p.Lys258Arg	missense_variant	Exon 6 of 14	1	NM_001318890.3	ENSP00000428047.1		Q08AH1-1

Frequencies

GnomAD3 genomes

AF:

0.0212

AC:

3224

AN:

152088

Hom.:

113

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0738

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00864

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00911

GnomAD3 exomes

AF:

0.00539

AC:

1352

AN:

250912

Hom.:

AF XY:

0.00375

AC XY:

508

AN XY:

135588

show subpopulations

Gnomad AFR exome

AF:

0.0741

Gnomad AMR exome

AF:

0.00310

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:

0.000168

Gnomad OTH exome

AF:

0.00360

GnomAD4 exome

AF:

0.00209

AC:

3051

AN:

1461584

Hom.:

111

Cov.:

AF XY:

0.00184

AC XY:

1340

AN XY:

727078

show subpopulations

Gnomad4 AFR exome

AF:

0.0738

Gnomad4 AMR exome

AF:

0.00338

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000162

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000101

Gnomad4 OTH exome

AF:

0.00480

GnomAD4 genome

AF:

0.0212

AC:

3233

AN:

152206

Hom.:

114

Cov.:

AF XY:

0.0206

AC XY:

1535

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.0738

Gnomad4 AMR

AF:

0.00863

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00901

Alfa

AF:

0.00439

Hom.:

Bravo

AF:

0.0233

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0713

AC:

314

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00666

AC:

808

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

May 24, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.63

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.0079

T;T

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.37

LIST_S2

Benign

0.45

.;T

MetaRNN

Benign

0.0027

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

L;L

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.0

N;N

REVEL

Benign

0.032

Sift

Benign

0.25

T;T

Sift4G

Benign

0.54

T;T

Polyphen

0.52

P;P

Vest4

0.23

MVP

0.53

MPC

0.29

ClinPred

0.0089

GERP RS

2.7

Varity_R

0.068

gMVP

0.48

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over