12-120737079-A-T

Variant names:

• chr12-120737079-A-T
• NM_000017.4:c.304A>T

Variant summary

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

The NM_000017.4(ACADS):​c.304A>T​(p.Met102Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,450,054 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. M102R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ACADS NM_000017.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.12

Genes affected

ACADS (HGNC:90): (acyl-CoA dehydrogenase short chain) This gene encodes a tetrameric mitochondrial flavoprotein, which is a member of the acyl-CoA dehydrogenase family. This enzyme catalyzes the initial step of the mitochondrial fatty acid beta-oxidation pathway. Mutations in this gene have been associated with short-chain acyl-CoA dehydrogenase (SCAD) deficiency. Alternative splicing results in two variants which encode different isoforms. [provided by RefSeq, Oct 2014]

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 chr12-120737080-T-G is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.36517388).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACADS	NM_000017.4	c.304A>T	p.Met102Leu	missense_variant	Exon 3 of 10	ENST00000242592.9	NP_000008.1
ACADS	NM_001302554.2	c.304A>T	p.Met102Leu	missense_variant	Exon 3 of 10		NP_001289483.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACADS	ENST00000242592.9	c.304A>T	p.Met102Leu	missense_variant	Exon 3 of 10	1	NM_000017.4	ENSP00000242592.4
ACADS	ENST00000411593.2	c.304A>T	p.Met102Leu	missense_variant	Exon 3 of 10	2		ENSP00000401045.2
ACADS	ENST00000539690.1	n.416A>T		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1450054 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 720174

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: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.014	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	13
DANN	Benign	0.82
DEOGEN2	Uncertain	0.75	D;D
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.37	T;T
MetaSVM	Uncertain	0.55	D
MutationAssessor	Benign	0.34	N;.
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.3	N;N
REVEL	Uncertain	0.30
Sift	Benign	0.24	T;T
Sift4G	Benign	0.31	T;T
Polyphen		0.0	B;B
Vest4		0.21
MutPred		0.56		Loss of helix (P = 0.2271);Loss of helix (P = 0.2271);
MVP		0.68
MPC		0.18
ClinPred		0.10	T
GERP RS		-2.7
Varity_R		0.24
gMVP		0.79

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-121174882;