Genetic Variant NM_000016.6:c.1A>G (chr1-75724788-A-G) – ACMG Classification: Pathogenic (14 pts)

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1PS1_ModeratePM2PP5_Moderate

The NM_000016.6(ACADM):c.1A>G(p.Met1?) variant causes a start lost 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. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ACADM
NM_000016.6 start_lost

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 1.25

Publications

0 publications found

Variant links:

COSMIC-nc: COSV63719542

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 67 pathogenic variants. Next in-frame start position is after 87 codons. Genomic position: 75732895. Lost 0.205 part of the original CDS.

PS1

Another start lost variant in NM_000016.6 (ACADM) was described as [Likely_pathogenic] in ClinVar

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-75724788-A-G is Pathogenic according to our data. Variant chr1-75724788-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 370802.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1A>G	p.Met1?	start_lost	Exon 1 of 12	NP_000007.1	A0A0S2Z366
ACADM	NM_001286043.2		c.1A>G	p.Met1?	start_lost	Exon 1 of 13	NP_001272972.1	Q5T4U5
ACADM	NM_001127328.3		c.1A>G	p.Met1?	start_lost	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.1A>G	p.Met1?	start_lost	Exon 1 of 12	ENSP00000359878.5	P11310-1
ACADM	ENST00000370834.9	TSL:1	c.1A>G	p.Met1?	start_lost	Exon 1 of 13	ENSP00000359871.5	Q5T4U5
ACADM	ENST00000420607.6	TSL:1	c.1A>G	p.Met1?	start_lost	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:

1370182

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

678766

African (AFR)

AF:

0.00

AC:

AN:

28348

American (AMR)

AF:

0.00

AC:

AN:

32776

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22598

East Asian (EAS)

AF:

0.00

AC:

AN:

32838

South Asian (SAS)

AF:

0.00

AC:

AN:

74880

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51432

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5420

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1065898

Other (OTH)

AF:

0.00

AC:

AN:

55992

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Medium-chain acyl-coenzyme A dehydrogenase deficiency (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Benign

(source)

DANN

Benign

0.78

DEOGEN2

Uncertain

0.43

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.76

FATHMM_MKL

Benign

0.29

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.88

MetaRNN

Pathogenic

0.98

MetaSVM

Uncertain

-0.039

PhyloP100

1.2

PROVEAN

Benign

-0.47

REVEL

Uncertain

0.43

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.0090

Vest4

0.65

MutPred

0.93

Gain of sheet (P = 0.0827)

MVP

0.72

ClinPred

0.99

GERP RS

0.84

PromoterAI

-0.70

Under-expression

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.92

gMVP

0.48

Mutation Taster

=7/193

disease causing (ClinVar)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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