chr12-120737875-C-T

Position:

chr12-120737875-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000017.4(ACADS):c.511C>T(p.Arg171Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0413 in 1,613,908 control chromosomes in the GnomAD database, including 1,595 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.032 ( 103 hom., cov: 33)

Exomes 𝑓: 0.042 ( 1492 hom. )

Consequence

ACADS
NM_000017.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:7O:2

Conservation

PhyloP100: 0.510

Variant links:

Genes affected

ACADS (HGNC:90): (acyl-CoA dehydrogenase short chain) This gene encodes a tetrameric mitochondrial flavoprotein, which is a member of the acyl-CoA dehydrogenase family. This enzyme catalyzes the initial step of the mitochondrial fatty acid beta-oxidation pathway. Mutations in this gene have been associated with short-chain acyl-CoA dehydrogenase (SCAD) deficiency. Alternative splicing results in two variants which encode different isoforms. [provided by RefSeq, Oct 2014]

ACADS 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=0.041048765).

BP6

Variant 12-120737875-C-T is Benign according to our data. Variant chr12-120737875-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-120737875-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0316 (4805/152176) while in subpopulation NFE AF= 0.0442 (3005/67976). AF 95% confidence interval is 0.0429. There are 103 homozygotes in gnomad4. There are 2345 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 103 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACADS	NM_000017.4 linkuse as main transcript	c.511C>T	p.Arg171Trp	missense_variant	5/10	ENST00000242592.9
ACADS	NM_001302554.2 linkuse as main transcript	c.473-174C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACADS	ENST00000242592.9 linkuse as main transcript	c.511C>T	p.Arg171Trp	missense_variant	5/10	1	NM_000017.4	P1
ACADS	ENST00000411593.2 linkuse as main transcript	c.473-174C>T		intron_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0316

AC:

4806

AN:

152058

Hom.:

103

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00949

Gnomad AMI

AF:

0.0373

Gnomad AMR

AF:

0.0332

Gnomad ASJ

AF:

0.0245

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00622

Gnomad FIN

AF:

0.0653

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0442

Gnomad OTH

AF:

0.0268

GnomAD3 exomes

AF:

0.0309

AC:

7750

AN:

250994

Hom.:

183

AF XY:

0.0310

AC XY:

4212

AN XY:

135720

show subpopulations

Gnomad AFR exome

AF:

0.00887

Gnomad AMR exome

AF:

0.0169

Gnomad ASJ exome

AF:

0.0227

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00568

Gnomad FIN exome

AF:

0.0636

Gnomad NFE exome

AF:

0.0443

Gnomad OTH exome

AF:

0.0363

GnomAD4 exome

AF:

0.0423

AC:

61903

AN:

1461732

Hom.:

1492

Cov.:

AF XY:

0.0414

AC XY:

30070

AN XY:

727170

show subpopulations

Gnomad4 AFR exome

AF:

0.00792

Gnomad4 AMR exome

AF:

0.0177

Gnomad4 ASJ exome

AF:

0.0241

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00692

Gnomad4 FIN exome

AF:

0.0625

Gnomad4 NFE exome

AF:

0.0485

Gnomad4 OTH exome

AF:

0.0382

GnomAD4 genome

AF:

0.0316

AC:

4805

AN:

152176

Hom.:

103

Cov.:

AF XY:

0.0315

AC XY:

2345

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.00946

Gnomad4 AMR

AF:

0.0331

Gnomad4 ASJ

AF:

0.0245

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00622

Gnomad4 FIN

AF:

0.0653

Gnomad4 NFE

AF:

0.0442

Gnomad4 OTH

AF:

0.0265

Alfa

AF:

0.0385

Hom.:

249

Bravo

AF:

0.0288

TwinsUK

AF:

0.0496

AC:

184

ALSPAC

AF:

0.0511

AC:

197

ESP6500AA

AF:

0.0104

AC:

ESP6500EA

AF:

0.0465

AC:

400

ExAC

AF:

0.0312

AC:

3787

Asia WGS

AF:

0.00606

AC:

AN:

3478

EpiCase

AF:

0.0403

EpiControl

AF:

0.0398

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:7Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Deficiency of butyryl-CoA dehydrogenase

Pathogenic:1Benign:6Other:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 30, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2001	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as likely benign. Following criteria are met: 0308 - Population frequency for this variant is out of keeping with known incidence of acyl-CoA dehydrogenase, short-chain, deficiency of (MIM#201470). (SB) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 27, 2023	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	The variant was identified in multiple GenomeConnect participants. Variant interpreted as Uncertain significance and reported on 05-17-2017 by Lab or GTR ID 303161. Variant was interpreted as Pathogenic and reported on 10-02-2015 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 04, 2018

This variant is associated with the following publications: (PMID: 29555771, 29678161, 28532786, 18523805, 9499414, 11134486, 16926354, 12220177) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

Eigen

Benign

-0.056

Eigen_PC

Benign

-0.21

FATHMM_MKL

Benign

0.33

LIST_S2

Uncertain

0.96

MetaRNN

Benign

0.041

MetaSVM

Uncertain

0.030

MutationAssessor

Uncertain

2.9

MutationTaster

Benign

0.00086

A;A

PrimateAI

Benign

0.32

PROVEAN

Uncertain

-4.3

REVEL

Benign

0.29

Sift

Uncertain

0.027

Sift4G

Uncertain

0.037

Polyphen

0.99

Vest4

0.15

MPC

0.21

ClinPred

0.063

GERP RS

2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.43

gMVP

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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