chr1-75761365-T-A

Position:

• chr1-75761365-T-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000016.6(ACADM):​c.1189T>A​(p.Tyr397Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,552 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: ACADM NM_000016.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.36

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.945
• PP5: Variant 1-75761365-T-A is Pathogenic according to our data. Variant chr1-75761365-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 226095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACADM	NM_000016.6	c.1189T>A	p.Tyr397Asn	missense_variant	11/12	ENST00000370841.9	NP_000007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACADM	ENST00000370841.9	c.1189T>A	p.Tyr397Asn	missense_variant	11/12	1	NM_000016.6	ENSP00000359878	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000360 AC: 9 AN: 250034 Hom.: 0 AF XY: 0.0000518 AC XY: 7 AN XY: 135194

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000490

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461552 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727060

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Medium-chain acyl-coenzyme A dehydrogenase deficiency Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 20, 2023	This sequence change replaces tyrosine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 397 of the ACADM protein (p.Tyr397Asn). This variant is present in population databases (rs759158371, gnomAD 0.05%). This missense change has been observed in individual(s) with MCAD deficiency (PMID: 18075239, 19064330, 21239873, 26947917). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.1189A>T. ClinVar contains an entry for this variant (Variation ID: 226095). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ACADM protein function. Experimental studies have shown that this missense change affects ACADM function (PMID: 26947917). This variant disrupts the p.Tyr397 amino acid residue in ACADM. Other variant(s) that disrupt this residue have been observed in individuals with ACADM-related conditions (PMID: 18075239, 19064330, 21239873, 26947917; Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 22, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 09, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Dec 20, 2023	PS3, PM3_Strong, PM2, PM1, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 26, 2023	Variant summary: ACADM c.1189T>A (p.Tyr397Asn) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase C-terminal domain (IPR009075) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 250034 control chromosomes (gnomAD). c.1189T>A has been reported in the literature as a biallelic genotype in individuals affected with Medium Chain Acyl-CoA Dehydrogenase Deficiency (e.g. Yokoi_2007, Woo_2011, Seo_2020, Li_2022). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, showing the variant had 0.9% residual activity when expressed in HEK293T cells (Hara_2016). The following publications have been ascertained in the context of this evaluation (PMID: 26947917, 36068006, 32901917, 21239873, 18075239). Two ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic, and one as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Uncertain	0.098	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.77	D;D;D;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Benign	0.24	.;N;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-7.4	D;D;D;D
REVEL	Pathogenic	0.84
Sift	Benign	0.28	T;T;T;T
Sift4G	Benign	0.25	T;T;T;T
Polyphen		1.0	D;P;B;B
Vest4		0.92
MutPred		0.85		.;.;Loss of catalytic residue at I429 (P = 0.0657);.;
MVP		0.94
MPC		0.96
ClinPred		0.52	D
GERP RS		5.3
Varity_R		0.78
gMVP		0.99

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

Publications

LitVar

Other links and lift over

dbSNP: rs759158371; hg19: chr1-76227050;