rs886041062

Variant names:

• chr1-156594021-GAAG-A
• rs886041062
• ENST00000368234.7:c.748_751delGAAGinsA

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM4_Supporting PP5

The ENST00000368234.7(NAXE):​c.748_751delGAAGinsA​(p.Glu250_Glu251delinsLys) variant causes a missense, conservative inframe deletion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: NAXE ENST00000368234.7 missense, conservative_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 5.80
• Publications: 4 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in ENST00000368234.7. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 1-156594021-GAAG-A is Pathogenic according to our data. Variant chr1-156594021-GAAG-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 268119.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NAXE	NM_144772.3	c.804_807delGAAGinsA	p.Lys269del	conservative_inframe_deletion, synonymous_variant	Exon 6 of 6	ENST00000368235.8	NP_658985.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NAXE	ENST00000368235.8	c.804_807delGAAGinsA	p.Lys269del	conservative_inframe_deletion, synonymous_variant	Exon 6 of 6	1	NM_144772.3	ENSP00000357218.3

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 1 Pathogenic:2 Uncertain:1

Mar 29, 2021

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Suma Genomics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 16, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.8
Mutation Taster		=20/180	disease causing

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs886041062; hg19: chr1-156563813;