12-111692741-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_025247.6(ACAD10):c.32G>A(p.Arg11His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000126 in 1,614,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R11C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: ACAD10 NM_025247.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.45

Genes affected

ACAD10 (HGNC:21597): (acyl-CoA dehydrogenase family member 10) This gene encodes a member of the acyl-CoA dehydrogenase family of enzymes (ACADs), which participate in the beta-oxidation of fatty acids in mitochondria. The encoded enzyme contains a hydrolase domain at the N-terminal portion, a serine/threonine protein kinase catlytic domain in the central region, and a conserved ACAD domain at the C-terminus. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined. [provided by RefSeq, Nov 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.031572104).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACAD10	NM_025247.6	c.32G>A	p.Arg11His	missense_variant	2/21	ENST00000313698.9
ACAD10	NM_001136538.2	c.32G>A	p.Arg11His	missense_variant	2/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACAD10	ENST00000313698.9	c.32G>A	p.Arg11His	missense_variant	2/21	1	NM_025247.6	P1

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000677 AC: 17 AN: 251132 Hom.: 0 AF XY: 0.0000663 AC XY: 9 AN XY: 135700

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000969

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000122 AC: 179 AN: 1461850 Hom.: 0 Cov.: 31 AF XY: 0.000118 AC XY: 86 AN XY: 727218

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00217

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000656

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152268 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74448

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000268 Hom.: 0

Bravo AF: 0.000230

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 11, 2023

The c.32G>A (p.R11H) alteration is located in exon 2 (coding exon 1) of the ACAD10 gene. This alteration results from a G to A substitution at nucleotide position 32, causing the arginine (R) at amino acid position 11 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	0.017
Dann	Benign	0.87
DEOGEN2	Benign	0.0019	T;.;.;.;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.23	T;T;T;.;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.032	T;T;T;T;T
MetaSVM	Benign	-0.38	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.15	N;N;N;D;N
REVEL	Benign	0.17
Sift	Benign	0.24	T;T;T;.;T
Sift4G	Benign	0.60	T;T;T;.;T
Polyphen		0.0	.;.;.;.;B
Vest4		0.11, 0.14, 0.12
MVP		0.51
MPC		0.17
ClinPred		0.014	T
GERP RS		-9.9
Varity_R		0.0083
gMVP		0.19

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

LitVar

Other links and lift over

dbSNP: rs146873324; hg19: chr12-112130545; COSMIC: COSV58156439;