13-110622219-TAGAA-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_001242882.2(NAXD):c.54_57del(p.Ala20PhefsTer9) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000943 in 1,611,596 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: NAXD NM_001242882.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 4.19

Genes affected

NAXD (HGNC:25576): (NAD(P)HX dehydratase) Enables ATP-dependent NAD(P)H-hydrate dehydratase activity. Predicted to be involved in metabolite repair. Predicted to be located in cytosol; endoplasmic reticulum; and mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 7 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-110622219-TAGAA-T is Pathogenic according to our data. Variant chr13-110622219-TAGAA-T is described in ClinVar as [Pathogenic]. Clinvar id is 617759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NAXD	NM_001242882.2	c.54_57del	p.Ala20PhefsTer9	frameshift_variant	2/10	ENST00000680254.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NAXD	ENST00000680254.1	c.54_57del	p.Ala20PhefsTer9	frameshift_variant	2/10		NM_001242882.2	P2

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152232 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000444 AC: 11 AN: 247992 Hom.: 0 AF XY: 0.0000224 AC XY: 3 AN XY: 134164

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000330

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000893

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000100 AC: 146 AN: 1459364 Hom.: 0 AF XY: 0.000103 AC XY: 75 AN XY: 725840

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000118

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152232 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74384

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000491

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

NAD(P)HX dehydratase deficiency Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The frameshift variant c.108_111del (p.Ala38PhefsTer9) has been reported previously in homozygous state in patients affected with NAXD deficiency (Van Bergen NJ. et al., 2019). This variant is reported with the allele frequency (0.004%) in the gnomAD and novel in 1000 genome database. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 19, 2020	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 2 of 10). (P) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 12 heterozygotes, 0 homozygotes). (P) 0703 - Comparable variants have moderate previous evidence for pathogenicity. Other variants predicted to cause NMD have been reported as pathogenic (PMID: 31755961, 32462209). (P) 0802 - Moderate previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported in patients with neurodegenerative disorder exacerbated by febrile illnesses. (ClinVar, PMID: 30576410, 32462209). (P) 1002 - Moderate functional evidence supporting abnormal protein function. Functional studies show that this variant causes impaired localisation of protein (PMID: 32462209). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

NAXD-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 13, 2024

The NAXD c.108_111delAAGA variant is predicted to result in a frameshift and premature protein termination (p.Ala38Phefs*9). This variant has been associated with NAD(P)HX dehydratase (NAXD) deficiency (reported as c.54_57delAAGA using another transcript in Van Bergen et al. 2019. PubMed ID: 30576410). This variant is reported in 0.0086% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in NAXD are expected to be pathogenic. This variant is interpreted as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 07, 2023

This variant is present in population databases (rs773887880, gnomAD 0.01%). For these reasons, this variant has been classified as Pathogenic. Studies have shown that this premature translational stop signal alters NAXD gene expression (PMID: 32462209). ClinVar contains an entry for this variant (Variation ID: 617759). This variant is also known as c.51_54delAGAA (p.Ala20Phefs*9). This premature translational stop signal has been observed in individuals with clinical features of progressive encephalopathy with brain edema and leukoencephalopathy (PMID: 30576410, 32462209). This sequence change creates a premature translational stop signal (p.Ala38Phefs*9) in the NAXD gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NAXD are known to be pathogenic (PMID: 30576410, 32462209). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs773887880; hg19: chr13-111274566;