chr1-75733603-C-T

Position:

chr1-75733603-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong

The ENST00000370841.9(ACADM):c.362C>T(p.Thr121Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,708 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 (★★). Synonymous variant affecting the same amino acid position (i.e. T121T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

ACADM
ENST00000370841.9 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 7.54

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in ENST00000370841.9

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.892

PP5

Variant 1-75733603-C-T is Pathogenic according to our data. Variant chr1-75733603-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3599.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 linkuse as main transcript	c.362C>T	p.Thr121Ile	missense_variant	5/12	ENST00000370841.9	NP_000007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACADM	ENST00000370841.9 linkuse as main transcript	c.362C>T	p.Thr121Ile	missense_variant	5/12	1	NM_000016.6	ENSP00000359878	P4	P11310-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251432

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1461708

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727186

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Medium-chain acyl-coenzyme A dehydrogenase deficiency

Pathogenic:11

Pathogenic, criteria provided, single submitter	curation	Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	Dec 30, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 08, 2023	- -
Pathogenic, criteria provided, single submitter	research	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Oct 04, 2024	PS3, PM3(strong), PM2,PP3 -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	May 03, 2017	- -
Likely pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 17, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2007	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 26, 2022	The p.Thr121Ile variant in ACADM has been reported in >20 individuals with MCAD deficiency (Nielsen 2007 PMID: 17273963, Nichols 2008 PMID: 18241067, Al-Hassnan 2010 PMID: 20567907). It was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. A study found that the p.Thr121Ile variant causes exon 5 skipping and a premature termination codon in exon 6 as well as decreased levels of mRNA in patient cells (Nielsen 2007 PMID: 17273963). An additional study showed that this variant reduces ACADM enzymatic activity (Andresen 2001 PMID: 11349232). This variant has also been reported in ClinVar (Variation ID 3599). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive MCAD deficiency. ACMG/AMP Criteria applied: PM3_VeryStrong, PS3_M, PP3, PM2_P. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 29, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 05, 2018	The ACADM c.362C>T; p.Thr121Ile variant (rs121434283), also known as T96I, has been described in the homozygous and compound heterozygous state in individuals affected with medium-chain acyl-coenzyme A dehydrogenase(MCAD) deficiency (Al-Hassnan 2010, Andresen 2001, Liang 2015, Nielsen 2007). It is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 3599) and is observed in the general population at a low overall frequency of 0.001% (3/246224 alleles) in the Genome Aggregation Database. Functional analyses of this variant demonstrate reduced enzymatic activity and skipping of exon 5 (Andresen 2001, Nielsen 2007). Based on available information, this variant is considered pathogenic. References: Al-Hassnan Z et al. Medium-chain acyl-CoA dehydrogenase deficiency in Saudi Arabia: incidence, genotype, and preventive implications. J Inherit Metab Dis. 2010 Dec;33 Suppl 3:S263-7. Andresen B et al. Medium-chain acyl-CoA dehydrogenase (MCAD) mutations identified by MS/MS-based prospective screening of newborns differ from those observed in patients with clinical symptoms: identification and characterization of a new, prevalent mutation that results in mild MCAD deficiency. Am J Hum Genet. 2001 Jun;68(6):1408-18. Liang C et al. First case report of medium-chain acyl-coenzyme A dehydrogenase deficiency in China. J Pediatr Endocrinol Metab. 2015 May;28(5-6):681-4. Nielsen K et al. Seemingly neutral polymorphic variants may confer immunity to splicing-inactivating mutations: a synonymous SNP in exon 5 of MCAD protects from deleterious mutations in a flanking exonic splicing enhancer. Am J Hum Genet. 2007 Mar;80(3):416-32. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 121 of the ACADM protein (p.Thr121Ile). This variant is present in population databases (rs121434283, gnomAD 0.004%). This missense change has been observed in individual(s) with MCAD deficiency (PMID: 11349232, 17273963, 20567907, 24966162, 25503862). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Saudi ancestry (PMID: 20567907). ClinVar contains an entry for this variant (Variation ID: 3599). 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: 11349232). Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 17273963). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 16, 2021	Variant summary: ACADM c.362C>T (p.Thr121Ile) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, N-terminal domain (IPR013786) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, at least one publication reports experimental evidence that this variant affects mRNA splicing and displays a high level of exon 5 skipping which leads to a premature termination codon in exon 6 (Nielsen_2007). The variant allele was found at a frequency of 1.2e-05 in 251932 control chromosomes (gnomAD and publication data). c.362C>T has been reported in the literature in the compound heterozygous and homozygous state in multiple individuals affected with Medium Chain Acyl-CoA Dehydrogenase Deficiency (Andresen_2001, Nielseri_2007, Nichols_2008, Al-Hassnan_2010, Tangeraas_2020). These data indicate that the variant is very likely to be associated with disease. At least one functional study reports this variant effect results in reducing ACADM enzymatic activity (Andresen_2001). Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1) and pathogenic (n=4). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 22, 2021

Functional studies demonstrated the variant resulted in skipping of exon 5 and premature termination and decreased medium chain acyl-CoA dehydrogenase activity compared to wild type (Nielsen et al., 2007); This variant is associated with the following publications: (PMID: 27535533, 31130284, 29268767, 24966162, 20567907, 17273963, 25503862, 11349232, 25525159) -

ACADM-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 16, 2024

The ACADM c.362C>T variant is predicted to result in the amino acid substitution p.Thr121Ile. This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with medium chain acyl-CoA dehydrogenase deficiency (see for example, Table 1, Andresen et al. 2001. PubMed ID: 11349232; Table 1, Liang et al. 2015. PubMed ID: 25503862; Table 1, Wen et al. 2022. PubMed ID: 35199448). This variant is reported in 0.0046% of alleles in individuals of European (Finnish) descent in gnomAD and it has been described as a founder variant in Saudi Arabia (Al-Hassnan et al. 2010. PubMed ID: 20567907). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.51

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.77

D;D;D;.

Eigen

Uncertain

0.61

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D;D

M_CAP

Pathogenic

0.40

MetaRNN

Pathogenic

0.89

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

2.0

.;M;.;.

MutationTaster

Benign

1.0

A;A;A;A;A

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-4.4

D;D;D;D

REVEL

Pathogenic

0.87

Sift

Uncertain

0.018

D;D;D;D

Sift4G

Benign

0.14

T;T;T;T

Polyphen

0.60

P;P;P;P

Vest4

0.96

MutPred

0.67

.;.;Gain of sheet (P = 0.1208);.;

MVP

0.97

MPC

0.41

ClinPred

0.96

GERP RS

5.7

Varity_R

0.89

gMVP

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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