chr1-75724802-C-A

Position:

• chr1-75724802-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000016.6(ACADM):​c.15C>A​(p.Phe5Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ACADM NM_000016.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -1.91

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09127885).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACADM	NM_000016.6	c.15C>A	p.Phe5Leu	missense_variant	1/12	ENST00000370841.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACADM	ENST00000370841.9	c.15C>A	p.Phe5Leu	missense_variant	1/12	1	NM_000016.6	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1368108 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 676926

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jul 18, 2017

The ACADM c.15C>A; p.Phe5Leu variant, to our knowledge, has not been reported in the literature or gene-specific variant databases, nor reported in the general population databases (Exome Variant Server, Genome Aggregation Database). The phenylalanine at codon 5 is weakly conserved, and computational algorithms (SIFT, MutationTaster, Align GVGD) predict this variant to be tolerated. However, due to the lack of information regarding p.Phe5Leu, its clinical significance is uncertain at this time. -

Medium-chain acyl-coenzyme A dehydrogenase deficiency Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Oct 06, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	6.7
DANN	Benign	0.72
DEOGEN2	Benign	0.38	T;T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.59	T;T;T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.091	T;T;T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	0.81	L;.;L
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	0.18	N;N;N
REVEL	Benign	0.21
Sift	Benign	0.71	T;T;T
Sift4G	Benign	0.30	T;T;D
Polyphen		0.0	B;B;B
Vest4		0.26
MutPred		0.40		Gain of helix (P = 0.0022);Gain of helix (P = 0.0022);Gain of helix (P = 0.0022);
MVP		0.53
MPC		0.22
ClinPred		0.068	T
GERP RS		-2.8
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.045
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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

Other links and lift over

dbSNP: rs1024056446; hg19: chr1-76190487;