2-200595281-C-T

Position:

• chr2-200595281-C-T

Variant summary

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

The NM_001159.4(AOX1):​c.113C>T​(p.Thr38Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,460,364 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: AOX1 NM_001159.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.39

Genes affected

AOX1 (HGNC:553): (aldehyde oxidase 1) Aldehyde oxidase produces hydrogen peroxide and, under certain conditions, can catalyze the formation of superoxide. Aldehyde oxidase is a candidate gene for amyotrophic lateral sclerosis. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AOX1	NM_001159.4	c.113C>T	p.Thr38Ile	missense_variant	3/35	ENST00000374700.7	NP_001150.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AOX1	ENST00000374700.7	c.113C>T	p.Thr38Ile	missense_variant	3/35	1	NM_001159.4	ENSP00000363832.2
AOX1	ENST00000454629.1	c.38C>T	p.Thr13Ile	missense_variant	3/7	5		ENSP00000392485.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460364 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726512

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

May 26, 2022

The c.113C>T (p.T38I) alteration is located in exon 3 (coding exon 3) of the AOX1 gene. This alteration results from a C to T substitution at nucleotide position 113, causing the threonine (T) at amino acid position 38 to be replaced by an isoleucine (I). 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	0.25
BayesDel_addAF	Uncertain	0.036	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D;T
Eigen	Uncertain	0.34
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.049	D
MetaRNN	Uncertain	0.56	D;D
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Pathogenic	3.2	M;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-4.8	D;D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0080	D;D
Sift4G	Uncertain	0.0080	D;D
Polyphen		1.0	D;.
Vest4		0.65
MutPred		0.50		Loss of phosphorylation at T38 (P = 0.0579);.;
MVP		0.56
MPC		0.51
ClinPred		0.99	D
GERP RS		3.9
Varity_R		0.59
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.20		Position offset: -9

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: chr2-201460004;