rs759158371

Variant names:

• chr1-75761365-T-A
• rs759158371
• NM_000016.6:c.1189T>A

Your query was ambiguous. Multiple possible variants found:

• chr1-75761365-T-A
• chr1-75761365-T-G

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM5 PP2 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y397C) has been classified 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
• Publications: 7 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: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, ClinGen, Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000016.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-75761366-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3587922.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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.
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 226095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADM	NM_000016.6	MANE Select	c.1189T>A	p.Tyr397Asn	missense	Exon 11 of 12	NP_000007.1
	ACADM	NM_001286043.2		c.1288T>A	p.Tyr430Asn	missense	Exon 12 of 13	NP_001272972.1
	ACADM	NM_001127328.3		c.1201T>A	p.Tyr401Asn	missense	Exon 11 of 12	NP_001120800.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADM	ENST00000370841.9	TSL:1 MANE Select	c.1189T>A	p.Tyr397Asn	missense	Exon 11 of 12	ENSP00000359878.5
	ACADM	ENST00000370834.9	TSL:1	c.1288T>A	p.Tyr430Asn	missense	Exon 12 of 13	ENSP00000359871.5
	ACADM	ENST00000420607.6	TSL:1	c.1201T>A	p.Tyr401Asn	missense	Exon 11 of 12	ENSP00000409612.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000360 AC: 9 AN: 250034 AF XY: 0.0000518

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53262

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111870

Other (OTH) AF: 0.0000166 AC: 1 AN: 60390

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

May 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 with a negative predictive value of 80%. 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.

Apr 26, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Jul 22, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 09, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 20, 2023

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PM3_Strong, PM2, PM1, PP3

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Benign	0.24	N
PhyloP100		7.4
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-7.4	D
REVEL	Pathogenic	0.84
Sift	Benign	0.28	T
Sift4G	Benign	0.25	T
Polyphen		1.0	D
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
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: rs759158371; hg19: chr1-76227050;