NM_000016.6:c.199T>C

Variant names:

• chr1-75732724-T-C
• rs121434280
• NM_000016.6:c.199T>C
• ACADM p.Tyr67His

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+11 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21
• Conservation: PhyloP100: 5.80
• Publications: 35 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: PanelApp Australia, Orphanet, ClinGen, G2P, Labcorp Genetics (formerly Invitae), Natera

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 11 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		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).
	PM2Absent/extremely low in population databases		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.
	PM5Novel missense at known pathogenic residue		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)
	PP5Reputable source reports pathogenic		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

Sel.	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	Prot: NP_000007.1 UniProt:
	ACADM NM_001286043.2		c.199T>C p.Tyr67His	missense	Exon 3 of 13	Prot: NP_001272972.1 UniProt:
	ACADM NM_001127328.3		c.211T>C p.Tyr71His	missense	Exon 3 of 12	Prot: NP_001120800.1 UniProt:

ACADM NM_000016.6

MANE Select

HGVSc / HGVSpc.199T>Cp.Tyr67His

Exon rankExon 3 of 12

missense

Prot: NP_000007.1UniProt: A0A0S2Z366P11310-1

ACADM NM_001286043.2

HGVSc / HGVSpc.199T>Cp.Tyr67His

Exon rankExon 3 of 13

missense

Prot: NP_001272972.1UniProt: Q5T4U5

ACADM NM_001127328.3

HGVSc / HGVSpc.211T>Cp.Tyr71His

Exon rankExon 3 of 12

missense

Prot: NP_001120800.1UniProt: P11310-2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	ACADM ENST00000370841.9	TSL:1MANE Select	c.199T>C p.Tyr67His	missense	Exon 3 of 12	Prot: ENSP00000359878.5 UniProt:
	ACADM ENST00000370834.9	TSL:1	c.199T>C p.Tyr67His	missense	Exon 3 of 13	Prot: ENSP00000359871.5 UniProt:
	ACADM ENST00000420607.6	TSL:1	c.211T>C p.Tyr71His	missense	Exon 3 of 12	Prot: ENSP00000409612.2 UniProt:

ACADM ENST00000370841.9

TSL:1MANE Select

HGVSc / HGVSpc.199T>Cp.Tyr67His

Exon rankExon 3 of 12

missense

Prot: ENSP00000359878.5UniProt: P11310-1

ACADM ENST00000370834.9

TSL:1

HGVSc / HGVSpc.199T>Cp.Tyr67His

Exon rankExon 3 of 13

missense

Prot: ENSP00000359871.5UniProt: Q5T4U5

ACADM ENST00000420607.6

TSL:1

HGVSc / HGVSpc.211T>Cp.Tyr71His

Exon rankExon 3 of 12

missense

Prot: ENSP00000409612.2UniProt: P11310-2

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.000690	AC:105	Hom:0	AN:152246	Cov:33
GnomAD2 exomes	AF: 0.000501	AC:126	Hom:	AN:251294	Cov:
GnomAD4 exome	AF: 0.000838	AC:1225	Hom:0	AN:1461554	Cov:30
GnomAD4 genome	AF: 0.000690	AC:105	Hom:0	AN:152246	Cov:33
TOPMed (Bravo)	AF: 0.000706	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.000780	AC:387	Hom:0	AN:496242	Cov:
Local & regional cohorts 2 sources Population-specific and national genomic databases
ESP6500 (Exome Variant Server)	AF: 0.000846	AC:11	Hom:	AN:13004	Cov:
UK10K	AF: 0.000529	AC:4	Hom:	AN:7562	Cov:

Showing 8 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.00144 *	16	11112	0.00176 *	31	17616
BipEx(Bipolar disorder (including schizoaffective))	0.000844	24	28420	0.000763	22	28844
Epi25(Epilepsy)	0.000620	26	41958	0.000583	39	66888
SCHEMA(Schizophrenia)	0.000542	66	121820	0.000478	91	190544

Showing 4 cohortsAllele 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

Pathogenic	VUS	Benign	Condition
16	-	-	Medium-chain acyl-coenzyme A dehydrogenase deficiency (16)
4	-	-	not provided (4)
1	-	-	Inborn genetic diseases (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	24
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Uncertain	0.030
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.63	D
Eigen	Benign	-0.13
Eigen_PC	Benign	0.054
FATHMM_MKL	Pathogenic	0.99	D
FuncVEP CTI	Benign	0.29
GPN-Star LLR	N/A	-4.5
GPN-Star score	N/A	4.5
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.020	T
MetaSVM	Pathogenic	0.88	D
Mutation Taster	N/A	1/99	disease causing (ClinVar)
MutationAssessor	Benign	0.49	N
PhyloP100	Uncertain	5.8
popEVE	Benign	-2.7
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.56
Sift	Benign	0.29	T
Sift4G	Benign	0.37	T
Varity_R	N/A	0.47
VESM-3B	Benign	-7.5

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs121434280;

hg19: chr1-76198409;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar