NXN

protein-coding

nucleoredoxin, the group of Nucleoredoxin family

Gene summary

This gene encodes a member of the thioredoxin superfamily, a group of small, multifunctional redox-active proteins. Members of this family are characterized by a conserved active motif called the thioredoxin fold that catalyzes disulfide bond formation and isomerization. The encoded protein acts a redox-dependent regulator of the Wnt signaling pathway and is involved in cell growth and differentiation. [provided by RefSeq, Sep 2015]

MANE transcript

NM_022463.5

Inheritance

ClinVar variants

P:6U:90B:74

Top phenotype

Robinow syndrome, autosomal recessive 2

gnomAD constraint

pLI —, LoF o/e 0.05

Max pathogenic AF

—

Genomic locus

chr17:799,310-979,776

External References & Databases

Ensembl (ENSG00000167693)

Transcript & Mutation Effects

hg38 • Region Span ~180.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

robinow syndrome, autosomal recessive 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032800

Submitter: Labcorp Genetics (formerly Invitae)

robinow syndrome, autosomal recessive 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032800

Submitter: PanelApp Australia

robinow syndrome, autosomal recessive 2MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0032800

Submitter: Ambry Genetics

autosomal recessive Robinow syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009999

Submitter: Orphanet

Clinical Genomic Database (CGD)

Robinow syndrome, autosomal recessive 2AR

Manifestation: Cardiovascular; Craniofacial; Musculoskeletal

Intervention: Cardiovascular

Rationale: The condition can involve congenital cardiac anomalies, and awareness may allow early management

Refs: 29276006

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NXN variants in ClinVar

5 Conditions Cataloged

not providedTotal: 181

not specifiedTotal: 65

NXN-related disorderTotal: 15

Robinow syndrome, autosomal recessive 2Total: 6

Distal shortening of limbsTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_022463.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	63 clinvar	7 clinvar	71
missense			88 clinvar	3 clinvar	1 clinvar	92
nonsense	3 clinvar	1 clinvar				4
start loss						0
frameshift	2 clinvar		1 clinvar			3
splice donor/acceptor (+/-2bp)						0
Total	5	1	90	66	8	170

Highest pathogenic variant AF is 0.000006661604

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 14 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_022463.5	RefSeq	NP_071908.2	8	MANE Select
ENST00000336868.8	Ensembl	ENSP00000337443.3	8	MANE Select
NM_001205319.1	RefSeq	NP_001192248.1	8	Standard
ENST00000537628.6	Ensembl	ENSP00000446446.2	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

miR-targeted genes in epithelium - TarBase
miR-targeted genes in lymphocytes - TarBase
miR-targeted genes in muscle cell - TarBase

Biological Process

Wnt signaling pathway
cell differentiation
negative regulation of Wnt signaling pathway
negative regulation of protein ubiquitination
cell redox homeostasis

Molecular Function

thioredoxin-disulfide reductase activity
protein-disulfide reductase activity

Cellular Component

nucleus
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000336868
Coding exons: 8
Length: 180458
Individuals with no LoFs: 125728
Homozygous LoFs: 0
Heterozygous LoFs: 4
Defined: 125732
p: 0.0000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.18	155	252	0.614	0.0000162	2779
Missense (PolyPhen)		41	81.159	0.50518		890
Synonymous	0.922	101	113	0.890	0.00000778	892
Loss of Function	4.12	1	21.7	0.0460	0.00000125	221

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0.000051	0.000046	rare
European (Non-Finnish)	0.000019	0.000018	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Functions as a redox-dependent negative regulator of the Wnt signaling pathway, possibly by preventing ubiquitination of DVL3 by the BCR(KLHL12) complex. May also function as a transcriptional regulator act as a regulator of protein phosphatase 2A (PP2A) (By similarity). {ECO:0000250}.;

Recessive Scores

pRec: 0.116

Intolerance Scores

LoFtool: 0.0963
RVIS EVS: -0.82
RVIS percentile EVS: 11.77

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.881

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium