chr1-75732724-TAT-AAC

Variant names:

• chr1-75732724-TAT-AAC
• NM_000016.6:c.199_201delTATinsAAC
• ACADM p.Tyr67Asn

GermlineCancer (beta)

Variant summary

Our verdict is Likely pathogenic.

+6 Likely Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 6 classification points (ACMG Germline Pathogenicity v2019). PM1PM2PM5

The NM_000016.6(ACADM):c.199_201delTATinsAAC (p.Tyr67Asn) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. 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)
• Consequence: ACADM NM_000016.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.96
• Publications: 0 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 6 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		Absent from gnomAD (AR/unknown gene) — PM2; Absent from gnomAD at well-covered site (MOI: AR) (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)

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.199_201delTATinsAAC p.Tyr67Asn	missense	N/A	Prot: NP_000007.1 UniProt:
	ACADM NM_001286043.2		c.199_201delTATinsAAC p.Tyr67Asn	missense	N/A	Prot: NP_001272972.1 UniProt:
	ACADM NM_001127328.3		c.211_213delTATinsAAC p.Tyr71Asn	missense	N/A	Prot: NP_001120800.1 UniProt:

ACADM NM_000016.6

MANE Select

HGVSc / HGVSpc.199_201delTATinsAACp.Tyr67Asn

Exon rankN/A

missense

Prot: NP_000007.1UniProt: A0A0S2Z366P11310-1

ACADM NM_001286043.2

HGVSc / HGVSpc.199_201delTATinsAACp.Tyr67Asn

Exon rankN/A

missense

Prot: NP_001272972.1UniProt: Q5T4U5

ACADM NM_001127328.3

HGVSc / HGVSpc.211_213delTATinsAACp.Tyr71Asn

Exon rankN/A

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.199_201delTATinsAAC p.Tyr67Asn	missense	N/A	Prot: ENSP00000359878.5 UniProt:
	ACADM ENST00000370834.9	TSL:1	c.199_201delTATinsAAC p.Tyr67Asn	missense	N/A	Prot: ENSP00000359871.5 UniProt:
	ACADM ENST00000420607.6	TSL:1	c.211_213delTATinsAAC p.Tyr71Asn	missense	N/A	Prot: ENSP00000409612.2 UniProt:

ACADM ENST00000370841.9

TSL:1MANE Select

HGVSc / HGVSpc.199_201delTATinsAACp.Tyr67Asn

Exon rankN/A

missense

Prot: ENSP00000359878.5UniProt: P11310-1

ACADM ENST00000370834.9

TSL:1

HGVSc / HGVSpc.199_201delTATinsAACp.Tyr67Asn

Exon rankN/A

missense

Prot: ENSP00000359871.5UniProt: Q5T4U5

ACADM ENST00000420607.6

TSL:1

HGVSc / HGVSpc.211_213delTATinsAACp.Tyr71Asn

Exon rankN/A

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 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Uncertain	7.0

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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

hg19: chr1-76198409;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar