rs886041062

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 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

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a chain NAD(P)H-hydrate epimerase (size 240) in uniprot entity NNRE_HUMAN there are 9 pathogenic changes around while only 2 benign (82%) in NM_144772.3
• 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 id is 268119.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=2}.

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

May 16, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Suma Genomics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs886041062; hg19: chr1-156563813;