chr1-75749509-G-A

Variant names:

• chr1-75749509-G-A
• rs121434274
• NM_000016.6:c.799G>A

Variant summary

Our verdict is Pathogenic. The variant received 27 ACMG points: 27P and 0B. PS1_Very_Strong PS3 PM1 PP2 PP3_Strong PP5_Very_Strong

The NM_000016.6(ACADM):​c.799G>A​(p.Gly267Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000209 in 1,613,900 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000268497: Functional analyses of the variant protein show a significant reduction in enzymatic activity (Andresen 1997, Zschocke 2001)." and additional evidence is available in ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G267V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: ACADM NM_000016.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:28
• Conservation: PhyloP100: 9.76
• Publications: 24 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 27 ACMG points.

• PS1: Transcript NM_000016.6 (ACADM) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000268497: Functional analyses of the variant protein show a significant reduction in enzymatic activity (Andresen 1997, Zschocke 2001).; SCV000630297: Experimental studies have shown that this missense change affects ACADM function (PMID: 9158144, 24966162).; SCV000693959: at least one functional study (Sturm_2012).; SCV000915432: Expression studies of the p.Gly267Arg variant in E. coli revealed considerable residual MCAD activity of the protein (40%) compared to wild type (Andresen et al. 1997). In vitro activity of the p.Gly267Arg protein was markedly increased when co-expressed with GroESL chaperonins, indicating that the variant affects protein folding (Andresen et al. 1997).; SCV000967652: "In vitro functional studies suggest that the p.Gly271Arg variant leads to reduced activity." PMID:11409868, PMID:23028790, PMID:24966162; SCV002058496: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 24966162, 9158144, PS3_S).; SCV005423836: Functional studies in fibroblasts confirm this variant reduces significatively MCAD´s activity (PMID: 23028790).; SCV000238583: Expression studies demonstrate a reduced (13% to less than 10%) residual MCAD enzyme activity compared to wild-type and reduced protein expression on western blot analysis (Koster et al., 2014; Sturm et al., 2012); SCV004116568: In functional studies, the MCAD protein levels and enzyme activity were significantly reduced (Sturm et al. 2012. PubMed ID: 23028790; Koster et al. 2014. PubMed ID: 24966162).
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972
• PP5: Variant 1-75749509-G-A is Pathogenic according to our data. Variant chr1-75749509-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 3588.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADM	NM_000016.6	MANE Select	c.799G>A	p.Gly267Arg	missense	Exon 9 of 12	NP_000007.1	A0A0S2Z366
	ACADM	NM_001286043.2		c.898G>A	p.Gly300Arg	missense	Exon 10 of 13	NP_001272972.1	Q5T4U5
	ACADM	NM_001127328.3		c.811G>A	p.Gly271Arg	missense	Exon 9 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.799G>A	p.Gly267Arg	missense	Exon 9 of 12	ENSP00000359878.5	P11310-1
	ACADM	ENST00000370834.9	TSL:1	c.898G>A	p.Gly300Arg	missense	Exon 10 of 13	ENSP00000359871.5	Q5T4U5
	ACADM	ENST00000420607.6	TSL:1	c.811G>A	p.Gly271Arg	missense	Exon 9 of 12	ENSP00000409612.2	P11310-2

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152110 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000215 AC: 54 AN: 251384 AF XY: 0.000228

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000273

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000219 AC: 320 AN: 1461790 Hom.: 0 Cov.: 31 AF XY: 0.000227 AC XY: 165 AN XY: 727200

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.000179 AC: 8 AN: 44720

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.000452 AC: 39 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

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

European-Non Finnish (NFE) AF: 0.000231 AC: 257 AN: 1111960

Other (OTH) AF: 0.000232 AC: 14 AN: 60382

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152110 Hom.: 0 Cov.: 33 AF XY: 0.0000942 AC XY: 7 AN XY: 74312

African (AFR) AF: 0.0000241 AC: 1 AN: 41416

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

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

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68010

Other (OTH) AF: 0.000479 AC: 1 AN: 2088

Alfa AF: 0.000164 Hom.: 0

Bravo AF: 0.000174

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000214 AC: 26

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
20	-	-	Medium-chain acyl-coenzyme A dehydrogenase deficiency (20)
6	-	-	not provided (6)
1	-	-	ACADM-related disorder (1)
1	-	-	Deficiency of butyryl-CoA dehydrogenase (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		9.8
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-7.7	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.91		Gain of MoRF binding (P = 0.0144)
MVP		0.98
MPC		0.81
ClinPred		0.76	D
GERP RS		5.7
Varity_R		0.97
gMVP		0.90
Mutation Taster		=0/100	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: rs121434274; hg19: chr1-76215194;