1-75762744-T-C

Position:

chr1-75762744-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The ENST00000370841.9(ACADM):c.1247T>C(p.Ile416Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000256 in 1,604,486 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. I416I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

ACADM
ENST00000370841.9 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:4

Conservation

PhyloP100: 6.91

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1

In a helix (size 13) in uniprot entity ACADM_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in ENST00000370841.9

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACADM	NM_000016.6 linkuse as main transcript	c.1247T>C	p.Ile416Thr	missense_variant	12/12	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.1247T>C	p.Ile416Thr	missense_variant	12/12	1	NM_000016.6	ENSP00000359878	P4	P11310-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000200

AC:

AN:

249404

Hom.:

AF XY:

0.0000296

AC XY:

AN XY:

135186

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.0000329

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000886

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000227

AC:

AN:

1452346

Hom.:

Cov.:

AF XY:

0.0000277

AC XY:

AN XY:

722962

show subpopulations

Gnomad4 AFR exome

AF:

0.0000902

Gnomad4 AMR exome

AF:

0.0000448

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000507

Gnomad4 SAS exome

AF:

0.0000234

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000199

Gnomad4 OTH exome

AF:

0.0000333

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152140

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000718

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Medium-chain acyl-coenzyme A dehydrogenase deficiency

Pathogenic:1Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 01, 2023	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 416 of the ACADM protein (p.Ile416Thr). This variant is present in population databases (rs760892123, gnomAD 0.006%). This missense change has been observed in individual(s) with mildly elevated levels of C8 and MCAD deficiency (PMID: 20434380, 23430840, 26947917; Invitae). ClinVar contains an entry for this variant (Variation ID: 203543). 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 expected to disrupt ACADM protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect ACADM function (PMID: 26947917). For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Mar 28, 2018	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Dec 06, 2021

Variant summary: ACADM c.1247T>C (p.Ile416Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 249404 control chromosomes (gnomAD), however the available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1247T>C has been reported in the literature in newborns and other individuals suspected with Medium Chain Acyl-CoA Dehydrogenase Deficiency (example: Smith_2010, Couce_2011, Couce_2013, Hara_2016, Tajima_2016, Adhikari_2020), but these data do not allow any conclusion about variant significance. Experimental evidence evaluating an impact on protein function demonstrated the variant has near normal residual enzymatic activity and thermal stability (Hara_2016). Three ClinVar submitters have assessed this variant since 2014: two have classified this variant as uncertain significance and one has classified it as pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance. -

See cases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Nov 13, 2019

ACMG classification criteria: PS3, PS4, PM2 -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 19, 2017

The I416T missense change in the ACADM gene has not been reported as a benign polymorphism. It has been reported previously in three patients detected by positive newborn screening results for medium chain acyl-CoA dehydrogenase (MCAD) deficiency who also harbored the K329E mutation (Smith et al., 2010 Couce et al., 2011). Biochemical analyses on these patients and in-silico analysis of I416T led the authors to conclude that this missense change was a variant of unknown significance. I416T is a non-conservative amino acid change in that a non-polar Isoleucine residue is replaced by a polar Threonine residue. This change occurs at a position that is highly conserved in the ACADM protein in mammals; however, this position is not highly conserved outside mammals or in related proteins. Multiple in-silico analysis models predict that I416T is a benign sequence change. Therefore, based on the currently available information, it is unclear whether I416T is a disease-causing mutation or a rare benign variant. The variant is found in ACADM panel(s). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Uncertain

0.068

BayesDel_noAF

Uncertain

0.040

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.37

T;D;T;.

Eigen

Benign

-0.14

Eigen_PC

Benign

0.059

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.77

T;T;T;T

M_CAP

Pathogenic

0.30

MetaRNN

Uncertain

0.44

T;T;T;T

MetaSVM

Uncertain

0.030

MutationAssessor

Benign

1.3

.;L;.;.

MutationTaster

Benign

0.99

D;D;D;D;D

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-2.5

D;D;D;D

REVEL

Uncertain

0.55

Sift

Benign

0.039

D;D;D;D

Sift4G

Benign

0.12

T;T;T;T

Polyphen

0.037

B;B;B;B

Vest4

0.31

MutPred

0.78

.;.;Loss of stability (P = 0.0062);.;

MVP

0.93

MPC

0.26

ClinPred

0.25

GERP RS

5.9

Varity_R

0.40

gMVP

0.89

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

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

Other links and lift over