chr1-75732724-T-A

Variant names:

• chr1-75732724-T-A
• rs121434280
• NM_000016.6:c.199T>A
• ACADM p.Tyr67Asn

GermlineCancer (beta)

Variant summary

Our verdict is Likely pathogenic.

+8 Likely Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 8 classification points (ACMG Germline Pathogenicity v2019). PM1PM2PM5PP3_Moderate

The NM_000016.6(ACADM):c.199T>A (p.Tyr67Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000000684 (AC=1) in the gnomAD database across 1,461,556 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000000899. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to 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)

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ACADM NM_000016.6 missense
• Clinical Significance: Not reported in ClinVar
• 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: Likely_pathogenic. The variant received 8 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM1Mutational hot spot or critical domain		Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 4 pathogenic, 1 benign (OR vs. background: 15.0).
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AR/unknown gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.000000899 — very rare for AR gene (base 0.001, raised to 0.005 by highest known P/LP ClinVar AF 0.00582) — PM2 moderate.
	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)
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).

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>A p.Tyr67Asn	missense	Exon 3 of 12	Prot: NP_000007.1 UniProt:
	ACADM NM_001286043.2		c.199T>A p.Tyr67Asn	missense	Exon 3 of 13	Prot: NP_001272972.1 UniProt:
	ACADM NM_001127328.3		c.211T>A p.Tyr71Asn	missense	Exon 3 of 12	Prot: NP_001120800.1 UniProt:

ACADM NM_000016.6

MANE Select

HGVSc / HGVSpc.199T>Ap.Tyr67Asn

Exon rankExon 3 of 12

missense

Prot: NP_000007.1UniProt: A0A0S2Z366P11310-1

ACADM NM_001286043.2

HGVSc / HGVSpc.199T>Ap.Tyr67Asn

Exon rankExon 3 of 13

missense

Prot: NP_001272972.1UniProt: Q5T4U5

ACADM NM_001127328.3

HGVSc / HGVSpc.211T>Ap.Tyr71Asn

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>A p.Tyr67Asn	missense	Exon 3 of 12	Prot: ENSP00000359878.5 UniProt:
	ACADM ENST00000370834.9	TSL:1	c.199T>A p.Tyr67Asn	missense	Exon 3 of 13	Prot: ENSP00000359871.5 UniProt:
	ACADM ENST00000420607.6	TSL:1	c.211T>A p.Tyr71Asn	missense	Exon 3 of 12	Prot: ENSP00000409612.2 UniProt:

ACADM ENST00000370841.9

TSL:1MANE Select

HGVSc / HGVSpc.199T>Ap.Tyr67Asn

Exon rankExon 3 of 12

missense

Prot: ENSP00000359878.5UniProt: P11310-1

ACADM ENST00000370834.9

TSL:1

HGVSc / HGVSpc.199T>Ap.Tyr67Asn

Exon rankExon 3 of 13

missense

Prot: ENSP00000359871.5UniProt: Q5T4U5

ACADM ENST00000420607.6

TSL:1

HGVSc / HGVSpc.211T>Ap.Tyr71Asn

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 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 exome	AF: 6.84e-7	AC:1	Hom:0	AN:1461556	Cov:30
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	24
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.78	D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
FuncVEP CTI	Pathogenic	0.62
GPN-Star LLR	N/A	-7.1
GPN-Star score	N/A	7.1
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	1.1	D
Mutation Taster	N/A	205/95	polymorphism
MutationAssessor	Pathogenic	3.0	M
PhyloP100	Uncertain	5.8
popEVE	Benign	-3.3
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.026	D
Varity_R	N/A	0.93
VESM-3B	Benign	-11

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