Variant 13-110622219-TAGAA-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_001242882.2(NAXD):c.54_57delAAGA(p.Ala20fs) 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

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 4.19

Variant links:

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]

NAXD links:

NAXD (HGNC:):

NAXD links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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. Fraction of 0.945 CDS is truncated, and there are 0 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	Protein	UniProt
NAXD	NM_001242882.2 linkuse as main transcript	c.54_57delAAGA	p.Ala20fs	frameshift_variant	2/10	ENST00000680254.1	NP_001229811.1	Q8IW45A0A7P0T9D8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NAXD	ENST00000680254.1 linkuse as main transcript	c.54_57delAAGA	p.Ala20fs	frameshift_variant	2/10		NM_001242882.2	ENSP00000505619.1		A0A7P0T9D8

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

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:

AN:

247992

Hom.:

AF XY:

0.0000224

AC XY:

AN XY:

134164

show subpopulations

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.:

AF XY:

0.000103

AC XY:

AN XY:

725840

show subpopulations

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:

AN:

152232

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74384

show subpopulations

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.:

Bravo

AF:

0.0000491

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

NAD(P)HX dehydratase deficiency

Pathogenic:4

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 -
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	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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.Ala20Phefs9). 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.Ala38Phefs9) 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). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 17, 2023	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Published functional studies demonstrate a loss of protein expression (Borna et al., 2020); This variant is associated with the following publications: (PMID: 32462209, 30576410) -

NAXD-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over