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 Uncertain significance.

+5 Uncertain · Hot

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 5 classification points (ACGS-UK Somatic Oncogenicity v2025). O1_ModerateO5_SupportingO7_SupportingO8_Supporting

The NM_000016.6(ACADM):c.199T>C (p.Tyr67His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The gene ACADM is a tumor suppressor gene (CancerMine: 2 TSG, 3 oncogene citations). The gene ACADM is a known oncogene (CancerMine: 2 TSG, 3 oncogene citations). 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 ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 5 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O1Established oncogenic variant		TSG gene: ClinVar germline P/LP ★★+ — Moderate (O1); O1 contributing sources (2.0 pts): ClinVar germline P/LP in TSG (★★)
	O5Same location/impact as known oncogenic		Different AA at same residue with oncogenic evidence (or germline P/LP in TSG), or same AA change SCI Tier II Potential — Supporting (O5); ClinVar same-AA oncogenic/T1: false | ClinVar same-AA SCI tier: — | CGI same-AA oncogenic: false | TSG: true | ClinVar same-AA germline P/LP: false | CIViC LOF: false | ClinVar diff-AA oncogenic: false | ClinVar diff-AA germline P/LP: true
	O7Mutational hotspot or critical domain		Supporting: cancerhotspots.org hit, critical domain, or missense neighbourhood hotspot; No cancerhotspots.org hit at this position; UniProt domain: 0 pathogenic, 0 benign.; ±8 AA neighbourhood: 4 pathogenic, 1 benign (OR vs. background: 15.0); Variant does not impact splicing — splice-hotspot path not applicable
	O8Missense constraint in gene or region		Missense in gene/domain constrained for missense variation where missense is common disease mechanism (O8 supporting); Gene/disease mechanism: missense is a common mechanism of oncogenesis; gnomAD missense Z-score: 0.42 (threshold ≥3.09 for constraint); Domain-level constraint: variant is in a critically constrained functional domain (IS_AT_CRITICAL_DOMAIN)

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