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rs77931234

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP3PP5_Moderate

The NM_000016.6(ACADM):c.985A>C(p.Lys329Gln) variant causes a missense change involving the alteration of a 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K329E) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

ACADM
NM_000016.6 missense

Scores

6
7
5

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 8.58
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 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 chr1-75761161-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3586.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.809
PP5
Variant 1-75761161-A-C is Pathogenic according to our data. Variant chr1-75761161-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 226057.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ACADMNM_000016.6 linkuse as main transcriptc.985A>C p.Lys329Gln missense_variant 11/12 ENST00000370841.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ACADMENST00000370841.9 linkuse as main transcriptc.985A>C p.Lys329Gln missense_variant 11/121 NM_000016.6 P4P11310-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Medium-chain acyl-coenzyme A dehydrogenase deficiency Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesFeb 20, 2015- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.25
BayesDel_addAF
Pathogenic
0.33
D
BayesDel_noAF
Pathogenic
0.23
Cadd
Uncertain
23
Dann
Uncertain
0.99
DEOGEN2
Uncertain
0.51
D;D;T;.
Eigen
Uncertain
0.27
Eigen_PC
Uncertain
0.40
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.99
D;D;D;D
M_CAP
Uncertain
0.088
D
MetaRNN
Pathogenic
0.81
D;D;D;D
MetaSVM
Uncertain
0.54
D
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Uncertain
0.59
T
PROVEAN
Benign
-0.64
N;N;N;N
REVEL
Pathogenic
0.71
Sift
Benign
0.17
T;T;T;T
Sift4G
Benign
0.50
T;T;T;T
Polyphen
0.83
P;B;P;P
Vest4
0.81
MutPred
0.66
.;.;Loss of ubiquitination at K362 (P = 0.0446);.;
MVP
0.99
MPC
0.21
ClinPred
0.90
D
GERP RS
5.2
Varity_R
0.44
gMVP
0.93

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.

Other links and lift over

dbSNP: rs77931234; hg19: chr1-76226846; API