rs121434280

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr1-75732724-T-C
• chr1-75732724-T-A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 15P and 1B. PS3 PM1 PP2 PP5_Very_Strong BP4

The NM_000016.6(ACADM):​c.199T>C​(p.Tyr67His) variant causes a missense change. The variant allele was found at a frequency of 0.000824 in 1,613,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as 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. Synonymous variant affecting the same amino acid position (i.e. Y67Y) has been classified 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:19
• Conservation: PhyloP100: 5.80
• Publications: 45 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: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: 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).
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_000016.6
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 95 curated pathogenic missense variants (we use a threshold of 10). The gene has 29 curated benign missense variants. Gene score misZ: 0.54287 (below the threshold of 3.09). Trascript score misZ: 0.41658 (below the threshold of 3.09). GenCC associations: The gene is linked to medium chain acyl-CoA dehydrogenase deficiency.
• PP5: Variant 1-75732724-T-C is Pathogenic according to our data. Variant chr1-75732724-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 3597.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.019735634). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

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

Sel.	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.: 0 Cov.: 33

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

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.: 0 Cov.: 30 AF XY: 0.000803 AC XY: 584 AN XY: 727096

African (AFR) AF: 0.0000896 AC: 3 AN: 33468

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86252

European-Finnish (FIN) AF: 0.0000936 AC: 5 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00108 AC: 1197 AN: 1111782

Other (OTH) AF: 0.000282 AC: 17 AN: 60376

GnomAD4 genome AF: 0.000690 AC: 105 AN: 152246 Hom.: 0 Cov.: 33 AF XY: 0.000645 AC XY: 48 AN XY: 74382

African (AFR) AF: 0.000145 AC: 6 AN: 41478

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000911 AC: 62 AN: 68036

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.000781 Hom.: 0

Bravo AF: 0.000706

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000610 AC: 74

EpiCase AF: 0.000872

EpiControl AF: 0.000889

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
14	-	-	Medium-chain acyl-coenzyme A dehydrogenase deficiency (14)
4	-	-	not provided (4)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
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
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.020	T
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Benign	0.49	N
PhyloP100		5.8
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.56
Sift	Benign	0.29	T
Sift4G	Benign	0.37	T
Polyphen		0.012	B
Vest4		0.56
MVP		0.99
MPC		0.26
ClinPred		0.056	T
GERP RS		4.5
Varity_R		0.47
gMVP		0.78
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs121434280; hg19: chr1-76198409;