rs121434278

Positions:

chr1-75740094-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000016.6(ACADM):c.583G>A(p.Gly195Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000745 in 1,611,412 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G195E) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000075 ( 1 hom. )

Consequence

ACADM
NM_000016.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 9.79

Variant links:

Genes affected

ACADM (HGNC:89): (acyl-CoA dehydrogenase medium chain) This gene encodes the medium-chain specific (C4 to C12 straight chain) acyl-Coenzyme A dehydrogenase. The homotetramer enzyme catalyzes the initial step of the mitochondrial fatty acid beta-oxidation pathway. Defects in this gene cause medium-chain acyl-CoA dehydrogenase deficiency, a disease characterized by hepatic dysfunction, fasting hypoglycemia, and encephalopathy, which can result in infantile death. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACADM links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000016.6

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-75740095-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2112467.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.971

PP5

Variant 1-75740094-G-A is Pathogenic according to our data. Variant chr1-75740094-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3594.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACADM	NM_000016.6 link	c.583G>A	p.Gly195Arg	missense_variant	7/12	ENST00000370841.9	NP_000007.1	P11310-1A0A0S2Z366

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACADM	ENST00000370841.9 link	c.583G>A	p.Gly195Arg	missense_variant	7/12	1	NM_000016.6	ENSP00000359878.5		P11310-1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251392

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135872

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000792

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000747

AC:

109

AN:

1459294

Hom.:

Cov.:

AF XY:

0.0000620

AC XY:

AN XY:

726012

show subpopulations

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:

0.0000856

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152118

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000162

Hom.:

Bravo

AF:

0.0000831

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Medium-chain acyl-coenzyme A dehydrogenase deficiency

Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 21, 2024	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 195 of the ACADM protein (p.Gly195Arg). This variant is present in population databases (rs121434278, gnomAD 0.007%). This missense change has been observed in individual(s) with medium-chain acyl-CoA dehydrogenase deficiency (PMID: 7603790, 16291504, 25940036). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Gly170Arg. ClinVar contains an entry for this variant (Variation ID: 3594). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ACADM protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ACADM function (PMID: 7929823, 9158144). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 20, 2015	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 1994	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 16, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 11, 2018	Variant summary: ACADM c.583G>A (p.Gly195Arg) results in a non-conservative amino acid change located in the Acyl-CoA oxidase/dehydrogenase, central domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 277130 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ACADM causing Medium Chain Acyl-CoA Dehydrogenase Deficiency (3.6e-05 vs 0.0054), allowing no conclusion about variant significance. The variant, c.583G>A, has been reported in the literature in multiple individuals affected with Medium Chain Acyl-CoA Dehydrogenase Deficiency (Andresen_1997, Gramer_2015). These data indicate that the variant is very likely to be associated with disease. A functional study, Andresen_1997, showed the variant eliminated enzyme activity. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Mar 24, 2014	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2022	Functional studies found that this variant is associated with no residual medium chain acyl-CoA dehydrogenase activity (Brackett et al., 1994.; Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25087612, 11524729, 18241067, 19224950, 7929823, 31012112, 32556492, 9158144, 33580884) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 13, 2013	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.90

D;D;D;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.96

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;D;D;D

M_CAP

Pathogenic

0.78

MetaRNN

Pathogenic

0.97

D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.1

.;H;.;.

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-6.8

D;D;D;D

REVEL

Pathogenic

0.99

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D

Polyphen

1.0

D;D;D;D

Vest4

0.99

MutPred

0.94

.;.;Gain of MoRF binding (P = 0.027);.;

MVP

0.99

MPC

0.81

ClinPred

1.0

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.99

gMVP

0.98

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