rs879255647

Variant names:

• chr1-156592199-C-A
• rs879255647
• NM_144772.3:c.281C>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_144772.3(NAXE):​c.281C>A​(p.Ala94Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 34)
• Consequence: NAXE NM_144772.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.91
• Publications: 5 publications found

Genes affected

NAXE (HGNC:18453): (NAD(P)HX epimerase) The product of this gene interacts with apolipoprotein A-I (apoA-I), the major apolipoprotein of high-density lipoproteins (HDLs). It is secreted into some bodily fluids, and its synthesis and secretion are stimulated in vitro by incubating cells with apoA-I. The human genome contains related pseudogenes. [provided by RefSeq, Jul 2008]

NAXE Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.899
• PP5: Variant 1-156592199-C-A is Pathogenic according to our data. Variant chr1-156592199-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 253145.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NAXE	NM_144772.3	c.281C>A	p.Ala94Asp	missense_variant	Exon 2 of 6	ENST00000368235.8	NP_658985.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NAXE	ENST00000368235.8	c.281C>A	p.Ala94Asp	missense_variant	Exon 2 of 6	1	NM_144772.3	ENSP00000357218.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 83

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy Pathogenic:1

Nov 14, 2016

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	.;T;.
Eigen	Pathogenic	0.78
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Uncertain	0.092	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Pathogenic	3.1	.;M;.
PhyloP100		5.9
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-5.5	D;D;D
REVEL	Uncertain	0.47
Sift	Uncertain	0.011	D;D;D
Sift4G	Uncertain	0.022	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.93
MutPred		0.70		Gain of ubiquitination at K97 (P = 0.0577);Gain of ubiquitination at K97 (P = 0.0577);Gain of ubiquitination at K97 (P = 0.0577);
MVP		0.45
MPC		1.3
ClinPred		1.0	D
GERP RS		3.6
PromoterAI		-0.059	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.95
gMVP		0.97
Mutation Taster		=6/94	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs879255647; hg19: chr1-156561991;