chr1-156593959-GC-G

Variant names:

• chr1-156593959-GC-G
• rs886041063
• NM_144772.3:c.743delC

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_144772.3(NAXE):​c.743delC​(p.Ala248GlufsTer26) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NAXE NM_144772.3 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.91
• 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: Likely_pathogenic. The variant received 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.143 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-156593959-GC-G is Pathogenic according to our data. Variant chr1-156593959-GC-G is described in ClinVar as Pathogenic. ClinVar VariationId is 268120.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAXE	NM_144772.3	MANE Select	c.743delC	p.Ala248GlufsTer26	frameshift	Exon 6 of 6	NP_658985.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAXE	ENST00000368235.8	TSL:1 MANE Select	c.743delC	p.Ala248GlufsTer26	frameshift	Exon 6 of 6	ENSP00000357218.3
	NAXE	ENST00000368234.7	TSL:1	c.687delC	p.Cys229fs	frameshift	Exon 6 of 6	ENSP00000357217.3
	NAXE	ENST00000969775.1		c.791delC	p.Ala264GlufsTer26	frameshift	Exon 6 of 6	ENSP00000639834.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 72

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.9
Mutation Taster		=3/197	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs886041063; hg19: chr1-156563751;