1-75728420-G-T

Variant names:

• chr1-75728420-G-T
• NM_000016.6:c.50G>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The NM_000016.6(ACADM):​c.50G>T​(p.Arg17Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 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. R17H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ACADM NM_000016.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.640

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-75728420-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 226078.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=3, Pathogenic=2}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.32642597).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACADM	NM_000016.6	c.50G>T	p.Arg17Leu	missense_variant	Exon 2 of 12	ENST00000370841.9	NP_000007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACADM	ENST00000370841.9	c.50G>T	p.Arg17Leu	missense_variant	Exon 2 of 12	1	NM_000016.6	ENSP00000359878.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460840 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726750

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: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	1.0
DANN	Benign	0.96
DEOGEN2	Uncertain	0.56	D;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.60	T;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.33	T;T;T
MetaSVM	Uncertain	-0.099	T
MutationAssessor	Benign	0.69	N;.;.
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.8	N;N;N
REVEL	Uncertain	0.38
Sift	Uncertain	0.023	D;D;D
Sift4G	Benign	0.061	T;D;T
Polyphen		0.0010	B;B;B
Vest4		0.51
MutPred		0.53		Loss of helix (P = 0.0167);Loss of helix (P = 0.0167);.;
MVP		0.68
MPC		0.23
ClinPred		0.086	T
GERP RS		-1.8
Varity_R		0.098
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-76194105;