1-75761161-A-G

Variant names:

• chr1-75761161-A-G
• rs77931234
• NM_000016.6:c.985A>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 13P and 2B. PM1 PM5 PP2 PP5_Very_Strong BP4 BS2_Supporting

The NM_000016.6(ACADM):​c.985A>G​(p.Lys329Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00582 in 1,614,074 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign 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. K329Q) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0061 (19 hom.)
• Consequence: ACADM NM_000016.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:52 O:1
• Conservation: PhyloP100: 8.58
• Publications: 154 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 11 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, 3 uncertain in NM_000016.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-75761161-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 226057.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.
• PP5: Variant 1-75761161-A-G is Pathogenic according to our data. Variant chr1-75761161-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 3586.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.041829288). . Strength limited to SUPPORTING due to the PP5.
• BS2: High Homozygotes in GnomAdExome4 at 19 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.985A>G	p.Lys329Glu	missense	Exon 11 of 12	NP_000007.1	A0A0S2Z366
	ACADM	NM_001286043.2		c.1084A>G	p.Lys362Glu	missense	Exon 12 of 13	NP_001272972.1	Q5T4U5
	ACADM	NM_001127328.3		c.997A>G	p.Lys333Glu	missense	Exon 11 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.985A>G	p.Lys329Glu	missense	Exon 11 of 12	ENSP00000359878.5	P11310-1
	ACADM	ENST00000370834.9	TSL:1	c.1084A>G	p.Lys362Glu	missense	Exon 12 of 13	ENSP00000359871.5	Q5T4U5
	ACADM	ENST00000420607.6	TSL:1	c.997A>G	p.Lys333Glu	missense	Exon 11 of 12	ENSP00000409612.2	P11310-2

Frequencies

GnomAD3 genomes AF: 0.00345 AC: 526 AN: 152254 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00235

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00619

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00333 AC: 836 AN: 251374 AF XY: 0.00302

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00106

Gnomad NFE exome AF: 0.00630

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00607 AC: 8872 AN: 1461700 Hom.: 19 Cov.: 31 AF XY: 0.00592 AC XY: 4306 AN XY: 727162

African (AFR) AF: 0.00131 AC: 44 AN: 33476

American (AMR) AF: 0.00114 AC: 51 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000804 AC: 21 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.000267 AC: 23 AN: 86256

European-Finnish (FIN) AF: 0.00146 AC: 78 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00756 AC: 8404 AN: 1111856

Other (OTH) AF: 0.00416 AC: 251 AN: 60392

GnomAD4 genome AF: 0.00345 AC: 526 AN: 152374 Hom.: 0 Cov.: 32 AF XY: 0.00323 AC XY: 241 AN XY: 74512

African (AFR) AF: 0.00113 AC: 47 AN: 41596

American (AMR) AF: 0.00235 AC: 36 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.000847 AC: 9 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00619 AC: 421 AN: 68034

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00555 Hom.: 9

Bravo AF: 0.00347

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.0101 AC: 39

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00744 AC: 64

ExAC AF: 0.00331 AC: 402

EpiCase AF: 0.00496

EpiControl AF: 0.00492

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
35	-	-	Medium-chain acyl-coenzyme A dehydrogenase deficiency (36)
12	-	-	not provided (12)
2	-	-	See cases (2)
1	-	-	ACADM-related disorder (1)
1	-	-	Epileptic spasm (1)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.44
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	-0.0086
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.042	T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	0.36	N
PhyloP100		8.6
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.68	N
REVEL	Pathogenic	0.69
Sift	Benign	0.21	T
Sift4G	Benign	0.67	T
Polyphen		0.83	P
Vest4		0.93
MVP		0.98
MPC		0.33
ClinPred		0.042	T
GERP RS		5.2
Varity_R		0.61
gMVP		0.96
Mutation Taster		=3/97	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: rs77931234; hg19: chr1-76226846; COSMIC: COSV99056894;