dbSNP rs121434280: ACADM:p.Tyr67His (chr1-75732724-T-C) – ACMG Classification: Pathogenic (11 pts)

Variant summary

Our verdict is The variant received 11 classification points (ACMG Germline Pathogenicity v2019). PS3PM2_SupportingPM5PP5_Strong

The NM_000016.6(ACADM):c.199T>C (p.Tyr67His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000824 (AC=1,330) in the gnomAD database across 1,613,800 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00103. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000056311: Functional analyses demonstrate that this variant results in a temperature-sensitive enzyme with partial activity (Jank 2014, Maier 2009, O'Reilly 2004). PMID:24718418. PMID:19224950. PMID:15479234." and additional evidence is available in ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.Y67C: Likely_pathogenic (ClinVar VariationId 4817899, 1 star) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.Y67= (synonymous): Uncertain_significance (ClinVar VariationId 4064602, 0 stars) This exact variant is curated in the UniProt human variants database as Uncertain Significance.

Frequency

Genomes: 𝑓 0.00069 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00084 ( 0 hom. )

Consequence

ACADM
NM_000016.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21

Conservation

PhyloP100: 5.80

Publications

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

ACADM links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000016.6, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 points.

PS3

Well-established functional study supports damaging effect (PS3); SCV000056311: Functional analyses demonstrate that this variant results in a temperature-sensitive enzyme with partial activity (Jank 2014, Maier 2009, O'Reilly 2004). PMID: 24718418. PMID: 19224950. PMID: 15479234.; SCV000630280: Experimental studies have shown that this missense change affects ACADM function (PMID: 15479234, 19224950, 24718418).; SCV000711420: In vitro functional studies provide some evidence that the p.Tyr71 variant may modestly impact protein function (O'Reilly 2004, Maier 2009, Koster 2014, Jank 2014, and Hara 2016).; SCV000238587: Published functional studies found this variant is associated with a mild reduction of enzyme activity at higher temperatures and partial rescue of enzyme activity with chaperonins suggesting this variant results in a mild folding defect (PMID: 11349232, 19224950, 24966162);; SCV000692632: PS3:Supporting; SCV003715394: Functional studies demonstrate that this is a temperature-sensitive mutation with mild effects on secondary protein structure and residual enzyme activity (Andresen, 2001; O'Reilly, 2004; Jank, 2014).

PM2

Rare in gnomAD for AR/unknown gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.00103 — borderline rare for AR gene (base 0.001, raised to 0.005 by highest known P/LP ClinVar AF 0.00582) — PM2 supporting.

PM5

Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.Y67C: Likely_pathogenic (ClinVar VariationId 4817899, 1 star); Other variants at the same amino acid residue (not pathogenic): p.Y67= (synonymous): Uncertain_significance (ClinVar VariationId 4064602, 0 stars)

PP5

ClinVar 2-star pathogenic — strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s). ClinVar submissions strongly and reliably favor pathogenicity (21/21 total P/LP).

Variant Effect in Transcripts

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

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACADM	NM_000016.6	MANE Select	c.199T>C	p.Tyr67His	missense	Exon 3 of 12	NP_000007.1	A0A0S2Z366
ACADM	NM_001286043.2		c.199T>C	p.Tyr67His	missense	Exon 3 of 13	NP_001272972.1	Q5T4U5
ACADM	NM_001127328.3		c.211T>C	p.Tyr71His	missense	Exon 3 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.199T>C	p.Tyr67His	missense	Exon 3 of 12	ENSP00000359878.5	P11310-1
ACADM	ENST00000370834.9	TSL:1	c.199T>C	p.Tyr67His	missense	Exon 3 of 13	ENSP00000359871.5	Q5T4U5
ACADM	ENST00000420607.6	TSL:1	c.211T>C	p.Tyr71His	missense	Exon 3 of 12	ENSP00000409612.2	P11310-2

Frequencies

GnomAD3 genomes

AF:

0.000690

AC:

105

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.0374

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000911

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000501

AC:

126

AN:

251294

AF XY:

0.000478

show subpopulations

Gnomad AFR exome

AF:

0.000309

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00103

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000838

AC:

1225

AN:

1461554

Hom.:

Cov.:

AF XY:

0.000803

AC XY:

584

AN XY:

727096

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33468

American (AMR)

AF:

0.0000224

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39654

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.0000936

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00108

AC:

1197

AN:

1111782

Other (OTH)

AF:

0.000282

AC:

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

124

186

248

310

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

144

192

240

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000690

AC:

105

AN:

152246

Hom.:

Cov.:

AF XY:

0.000645

AC XY:

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.000145

AC:

AN:

41478

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000911

AC:

AN:

68036

Other (OTH)

AF:

0.000478

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

TOPMed (Bravo)

AF:

0.000706

ALFA (dbGaP/dbSNP Allele Frequency Aggregator)

AF:

0.000780

AC:

387

AN:

496242

Hom.:

Local populations

ESP6500 (Exome Variant Server)

AF:

0.000846

AC:

AN:

13004

show subpopulations

European American

AF:

0.00105

AC:

AN:

8600

African American

AF:

0.000454

AC:

AN:

4404

UK10K

AF:

0.000529

AC:

AN:

7562

show subpopulations

TwinsUK

AF:

0.000560

AC:

AN:

3574

ALSPAC

AF:

0.000519

AC:

AN:

3854

Case/control cohorts

Cohort

Cases

Controls

ASC

(Autism)

16 / 11112AF: 0.00143988

31 / 17616AF: 0.00175976

BipEx

(Bipolar disorder (including schizoaffective))

24 / 28420AF: 0.000844476

22 / 28844AF: 0.000762724

Epi25

(Epilepsy)

26 / 41958AF: 0.000619667

39 / 66888AF: 0.000583064

SCHEMA

(Schizophrenia)

66 / 121820AF: 0.000541783

91 / 190544AF: 0.000477580

Allele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Medium-chain acyl-coenzyme A dehydrogenase deficiency (16)

not provided (4)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Uncertain

0.030

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.63

Eigen

Benign

-0.13

Eigen_PC

Benign

0.054

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

M_CAP

Pathogenic

0.32

MetaRNN

Benign

0.020

MetaSVM

Pathogenic

0.88

MutationAssessor

Benign

0.49

PhyloP100

5.8

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-2.4

REVEL

Uncertain

0.56

Sift

Benign

0.29

Sift4G

Benign

0.37

Varity_R

0.47

popEVE

Benign

-2.7

(source)

VESM-3B

Benign

-7.5

(source)

FuncVEP CTI

Benign

0.29

(source)

AlphaGenome AVI

Pathogenic

(source)

GPN-Star LLR

-4.5

(source)

GPN-Star score

4.5

(source)

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Pangolin (max)

Benign

0.010

(source)

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

Case/control cohorts

ClinVar

Computational scores

Splicing

Publications

Other links and lift over