Variant chr2-110798641-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001142807.4(ACOXL):c.377C>T(p.Ala126Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000582 in 1,613,970 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000060 ( 1 hom. )

Consequence

ACOXL
NM_001142807.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.57

Variant links:

Genes affected

ACOXL (HGNC:25621): (acyl-CoA oxidase like) Predicted to enable acyl-CoA oxidase activity; fatty acid binding activity; and flavin adenine dinucleotide binding activity. Predicted to be involved in fatty acid beta-oxidation using acyl-CoA oxidase and lipid homeostasis. Predicted to be located in peroxisomal matrix. Predicted to be active in peroxisome. [provided by Alliance of Genome Resources, Apr 2022]

ACOXL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.952

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACOXL	NM_001142807.4 linkuse as main transcript	c.377C>T	p.Ala126Val	missense_variant	6/18	ENST00000439055.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACOXL	ENST00000439055.6 linkuse as main transcript	c.377C>T	p.Ala126Val	missense_variant	6/18	2	NM_001142807.4		Q9NUZ1-4
ACOXL	ENST00000340561.8 linkuse as main transcript	c.377C>T	p.Ala126Val	missense_variant	6/11	1			Q9NUZ1-3
ACOXL	ENST00000676595.2 linkuse as main transcript	c.377C>T	p.Ala126Val	missense_variant	6/19			P1
ACOXL	ENST00000389811.8 linkuse as main transcript	c.377C>T	p.Ala126Val	missense_variant	6/19	5			Q9NUZ1-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000120

AC:

AN:

249572

Hom.:

AF XY:

0.000126

AC XY:

AN XY:

135396

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.000434

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000425

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000595

AC:

AN:

1461792

Hom.:

Cov.:

AF XY:

0.0000688

AC XY:

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000425

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000533

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000153

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.0000604

ExAC

AF:

0.000132

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 16, 2023

The c.377C>T (p.A126V) alteration is located in exon 6 (coding exon 5) of the ACOXL gene. This alteration results from a C to T substitution at nucleotide position 377, causing the alanine (A) at amino acid position 126 to be replaced by a valine (V). 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

Pathogenic

0.77

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.46

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.59

D;.;.

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.83

T;T;T

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.95

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.0

M;M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-3.8

D;D;D

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0020

D;D;D

Sift4G

Uncertain

0.0060

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.90

MutPred

0.80

Gain of catalytic residue at A126 (P = 0.0268);Gain of catalytic residue at A126 (P = 0.0268);Gain of catalytic residue at A126 (P = 0.0268);

MVP

0.85

MPC

0.71

ClinPred

0.80

GERP RS

5.3

Varity_R

0.46

gMVP

0.48

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over