1-75745808-A-T

Variant names:

• chr1-75745808-A-T
• rs875989871
• NM_000016.6:c.602A>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM1 PM2 PP2 BP4

The NM_000016.6(ACADM):​c.602A>T​(p.Tyr201Phe) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,534 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y201C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ACADM NM_000016.6 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.29
• Publications: 2 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: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000016.6
• PM2: Very rare variant in population databases, with high coverage
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.29691878).

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.602A>T	p.Tyr201Phe	missense splice_region	Exon 8 of 12	NP_000007.1	A0A0S2Z366
	ACADM	NM_001286043.2		c.701A>T	p.Tyr234Phe	missense splice_region	Exon 9 of 13	NP_001272972.1	Q5T4U5
	ACADM	NM_001127328.3		c.614A>T	p.Tyr205Phe	missense splice_region	Exon 8 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.602A>T	p.Tyr201Phe	missense splice_region	Exon 8 of 12	ENSP00000359878.5	P11310-1
	ACADM	ENST00000370834.9	TSL:1	c.701A>T	p.Tyr234Phe	missense splice_region	Exon 9 of 13	ENSP00000359871.5	Q5T4U5
	ACADM	ENST00000420607.6	TSL:1	c.614A>T	p.Tyr205Phe	missense splice_region	Exon 8 of 12	ENSP00000409612.2	P11310-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251348 AF XY: 0.00

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 FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458534 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725790

African (AFR) AF: 0.00 AC: 0 AN: 33380

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39634

South Asian (SAS) AF: 0.00 AC: 0 AN: 86164

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109092

Other (OTH) AF: 0.00 AC: 0 AN: 60292

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	23
DANN	Benign	0.74
DEOGEN2	Uncertain	0.68	D
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.071
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.30	T
MetaSVM	Uncertain	0.34	D
MutationAssessor	Benign	-0.32	N
PhyloP100		7.3
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.45
Sift	Benign	0.62	T
Sift4G	Benign	0.36	T
Polyphen		0.020	B
Vest4		0.52
MutPred		0.56		Loss of MoRF binding (P = 0.1006)
MVP		0.75
MPC		0.19
ClinPred		0.30	T
GERP RS		4.7
Varity_R		0.41
gMVP		0.64
Mutation Taster		=48/52	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs875989871; hg19: chr1-76211493;