3-132561170-C-A

Variant summary

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

The NM_032169.5(ACAD11):c.2049G>T(p.Lys683Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,390 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 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: 0.0000014 (0 hom.)
• Consequence: ACAD11 NM_032169.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.16

Genes affected

ACAD11 (HGNC:30211): (acyl-CoA dehydrogenase family member 11) This gene encodes an acyl-CoA dehydrogenase enzyme with a preference for carbon chain lengths between 20 and 26. Naturally occurring read-through transcription occurs between the upstream gene NPHP3 (nephronophthisis 3 (adolescent)) and this gene. [provided by RefSeq, Aug 2015]

NPHP3-ACAD11 (HGNC:):

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=0.25374734).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACAD11	NM_032169.5	c.2049G>T	p.Lys683Asn	missense_variant	18/20	ENST00000264990.11
NPHP3-ACAD11	NR_037804.1	n.6661G>T		non_coding_transcript_exon_variant	43/45

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACAD11	ENST00000264990.11	c.2049G>T	p.Lys683Asn	missense_variant	18/20	1	NM_032169.5	P1
ACAD11	ENST00000485198.5	c.*530G>T		3_prime_UTR_variant, NMD_transcript_variant	16/18	1
ACAD11	ENST00000469042.5	n.2835G>T		non_coding_transcript_exon_variant	16/18	2
ACAD11	ENST00000496418.5	n.2557G>T		non_coding_transcript_exon_variant	17/19	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 251004 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135624

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461390 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727004

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

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: 0.00000378

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

Feb 05, 2024

The c.2049G>T (p.K683N) alteration is located in exon 18 (coding exon 18) of the ACAD11 gene. This alteration results from a G to T substitution at nucleotide position 2049, causing the lysine (K) at amino acid position 683 to be replaced by an asparagine (N). 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	0.13
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Benign	-0.14
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.00087
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.25	T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	0.20	N
MutationTaster	Benign	0.92	N;N;N
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.40
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.023	D
Polyphen		0.41	B
Vest4		0.31
MutPred		0.64		Loss of MoRF binding (P = 0.0362);
MVP		0.91
MPC		0.22
ClinPred		0.46	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.31
gMVP		0.66

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: rs1456912128; hg19: chr3-132280014; COSMIC: COSV53898272;