Genetic Variant NM_000016.6:c.11G>A (chr1-75724798-G-A) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PM2PP2BP4_Strong

The NM_000016.6(ACADM):c.11G>A(p.Gly4Glu) 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 benign outcome for this variant. 16/22 in silico tools predict a benign 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. G4R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ACADM
NM_000016.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.140

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

medium chain acyl-CoA dehydrogenase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P

ACADM links:

ENSG00000293044 (HGNC:):

ENSG00000293044 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 95 curated pathogenic missense variants (we use a threshold of 10). The gene has 29 curated benign missense variants. Gene score misZ: 0.54287 (below the threshold of 3.09). Trascript score misZ: 0.41658 (below the threshold of 3.09). GenCC associations: The gene is linked to medium chain acyl-CoA dehydrogenase deficiency.

BP4

Computational evidence support a benign effect (MetaRNN=0.05962619).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000016.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACADM	NM_000016.6	MANE Select	c.11G>A	p.Gly4Glu	missense	Exon 1 of 12	NP_000007.1	A0A0S2Z366
ACADM	NM_001286043.2		c.11G>A	p.Gly4Glu	missense	Exon 1 of 13	NP_001272972.1	Q5T4U5
ACADM	NM_001127328.3		c.11G>A	p.Gly4Glu	missense	Exon 1 of 12	NP_001120800.1	P11310-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACADM	ENST00000370841.9	TSL:1 MANE Select	c.11G>A	p.Gly4Glu	missense	Exon 1 of 12	ENSP00000359878.5	P11310-1
ACADM	ENST00000370834.9	TSL:1	c.11G>A	p.Gly4Glu	missense	Exon 1 of 13	ENSP00000359871.5	Q5T4U5
ACADM	ENST00000420607.6	TSL:1	c.11G>A	p.Gly4Glu	missense	Exon 1 of 12	ENSP00000409612.2	P11310-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1369610

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

677836

African (AFR)

AF:

0.00

AC:

AN:

28480

American (AMR)

AF:

0.00

AC:

AN:

33622

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22600

East Asian (EAS)

AF:

0.00

AC:

AN:

32808

South Asian (SAS)

AF:

0.00

AC:

AN:

74738

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5436

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1064580

Other (OTH)

AF:

0.00

AC:

AN:

55936

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Uncertain

0.036

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Benign

0.73

DEOGEN2

Benign

0.39

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.033

LIST_S2

Benign

0.71

M_CAP

Benign

0.045

MetaRNN

Benign

0.060

MetaSVM

Benign

-0.29

MutationAssessor

Benign

0.34

PhyloP100

0.14

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.38

REVEL

Benign

0.20

Sift

Benign

0.89

Sift4G

Benign

0.89

Polyphen

0.0080

Vest4

0.15

MutPred

0.40

Gain of helix (P = 0.0093)

MVP

0.67

MPC

0.27

ClinPred

0.053

GERP RS

1.2

PromoterAI

0.16

Neutral

(source)

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.0

Varity_R

0.033

gMVP

0.30

Mutation Taster

=297/3

polymorphism

(source)

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

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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