NM_000016.6:c.477T>G

Variant names:

• chr1-75739988-T-G
• rs886038412
• NM_000016.6:c.477T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 9P and 2B. PM1 PM2 PP2 PP3_Strong BP6_Moderate

The NM_000016.6(ACADM):​c.477T>G​(p.Cys159Trp) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. C159C) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACADM NM_000016.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.932
• Publications: 1 publications found

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: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, ClinGen, Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000016.6
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974
• BP6: Variant 1-75739988-T-G is Benign according to our data. Variant chr1-75739988-T-G is described in CliVar as Benign. Clinvar id is 257514.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-75739988-T-G is described in CliVar as Benign. Clinvar id is 257514.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-75739988-T-G is described in CliVar as Benign. Clinvar id is 257514.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-75739988-T-G is described in CliVar as Benign. Clinvar id is 257514.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-75739988-T-G is described in CliVar as Benign. Clinvar id is 257514.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-75739988-T-G is described in CliVar as Benign. Clinvar id is 257514.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-75739988-T-G is described in CliVar as Benign. Clinvar id is 257514.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-75739988-T-G is described in CliVar as Benign. Clinvar id is 257514.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-75739988-T-G is described in CliVar as Benign. Clinvar id is 257514.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-75739988-T-G is described in CliVar as Benign. Clinvar id is 257514.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-75739988-T-G is described in CliVar as Benign. Clinvar id is 257514.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-75739988-T-G is described in CliVar as Benign. Clinvar id is 257514.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-75739988-T-G is described in CliVar as Benign. Clinvar id is 257514.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-75739988-T-G is described in CliVar as Benign. Clinvar id is 257514.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-75739988-T-G is described in CliVar as Benign. Clinvar id is 257514.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-75739988-T-G is described in CliVar as Benign. Clinvar id is 257514.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-75739988-T-G is described in CliVar as Benign. Clinvar id is 257514.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-75739988-T-G is described in CliVar as Benign. Clinvar id is 257514.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-75739988-T-G is described in CliVar as Benign. Clinvar id is 257514.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-75739988-T-G is described in CliVar as Benign. Clinvar id is 257514.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-75739988-T-G is described in CliVar as Benign. Clinvar id is 257514.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-75739988-T-G is described in CliVar as Benign. Clinvar id is 257514.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-75739988-T-G is described in CliVar as Benign. Clinvar id is 257514.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-75739988-T-G is described in CliVar as Benign. Clinvar id is 257514.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-75739988-T-G is described in CliVar as Benign. Clinvar id is 257514.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-75739988-T-G is described in CliVar as Benign. Clinvar id is 257514.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-75739988-T-G is described in CliVar as Benign. Clinvar id is 257514.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACADM	NM_000016.6	c.477T>G	p.Cys159Trp	missense_variant	Exon 7 of 12	ENST00000370841.9	NP_000007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACADM	ENST00000370841.9	c.477T>G	p.Cys159Trp	missense_variant	Exon 7 of 12	1	NM_000016.6	ENSP00000359878.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	D;D;D;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	.;M;.;.
PhyloP100		0.93
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-7.2	D;D;D;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.88
MutPred		0.78		.;.;Loss of catalytic residue at T194 (P = 0.0959);.;
MVP		0.98
MPC		0.87
ClinPred		0.83	D
GERP RS		4.2
Varity_R		0.96
gMVP		0.97
Mutation Taster		=4/96	disease causing

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

Other links and lift over

dbSNP: rs886038412; hg19: chr1-76205673;