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 NM_144772.3(NAXE):​c.804_807delGAAGinsA​(p.Lys269del) variant causes a conservative inframe deletion, synonymous change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E268E) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: NAXE NM_144772.3 conservative_inframe_deletion, synonymous
• 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 NM_144772.3. 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144772.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAXE	NM_144772.3	MANE Select	c.804_807delGAAGinsA	p.Lys269del	conservative_inframe_deletion synonymous	Exon 6 of 6	NP_658985.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAXE	ENST00000368234.7	TSL:1	c.748_751delGAAGinsA	p.Glu250_Glu251delinsLys	missense conservative_inframe_deletion	Exon 6 of 6	ENSP00000357217.3
	NAXE	ENST00000368235.8	TSL:1 MANE Select	c.804_807delGAAGinsA	p.Lys269del	conservative_inframe_deletion synonymous	Exon 6 of 6	ENSP00000357218.3
	NAXE	ENST00000969775.1		c.852_855delGAAGinsA	p.Lys285del	conservative_inframe_deletion synonymous	Exon 6 of 6	ENSP00000639834.1

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

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	1	-	Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 1 (3)
1	-	-	Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy (1)

Computational scores

Source: dbNSFP v4.9

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;