NIPAL4

protein-coding

NIPA like domain containing 4, the group of Solute carrier family 57, NIPA-like magnesium transporters

Gene summary

This gene likely encodes a membrane receptor. Mutations in this gene have been associated with autosomal recessive congenital ichthyosis. [provided by RefSeq, Feb 2010]

MANE transcript

NM_001099287.2

Inheritance

ClinVar variants

P:33U:87B:41

Top phenotype

Ichthyosis, congenital, autosomal recessive 6

gnomAD constraint

pLI —, LoF o/e 0.47

Max pathogenic AF

—

Genomic locus

chr5:157,460,213-157,474,722

External References & Databases

Ensembl (ENSG00000172548)

Transcript & Mutation Effects

hg38 • Region Span ~14.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive congenital ichthyosis 6DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012847

Submitter: G2P

autosomal recessive congenital ichthyosis 6STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012847

Submitter: PanelApp Australia

congenital non-bullous ichthyosiform erythrodermaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019306

Submitter: Orphanet

autosomal recessive congenital ichthyosis 6STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012847

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive congenital ichthyosis 6STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012847

Submitter: Genomics England PanelApp

lamellar ichthyosisSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017778

Submitter: Orphanet

autosomal recessive congenital ichthyosis 6DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012847

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Ichthyosis, congenital, autosomal recessive 6AR

Manifestation: Dermatologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 15317751; 17557927; 20301593

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NIPAL4 variants in ClinVar

12 Conditions Cataloged

not providedTotal: 76

Inborn genetic diseasesTotal: 58

Autosomal recessive congenital ichthyosis 6Total: 55

not specifiedTotal: 12

Lamellar ichthyosisTotal: 7

NIPAL4-related disorderTotal: 7

NIPAL4-related disordersTotal: 5

Autosomal recessive congenital ichthyosisTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001099287.2. 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			4 clinvar	28 clinvar	2 clinvar	34
missense	12 clinvar	4 clinvar	82 clinvar	10 clinvar	1 clinvar	109
nonsense	5 clinvar	2 clinvar	1 clinvar			8
start loss						0
frameshift	3 clinvar	3 clinvar				6
splice donor/acceptor (+/-2bp)	2 clinvar	2 clinvar				4
Total	22	11	87	38	3	161

Highest pathogenic variant AF is 0.0011123035

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 8 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001099287.2	RefSeq	NP_001092757.2	6	MANE Select
ENST00000311946.8	Ensembl	ENSP00000311687.8	6	MANE Select
NM_001172292.2	RefSeq	NP_001165763.2	5	Standard
ENST00000435489.7	Ensembl	ENSP00000406456.3	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Transport of small molecules
Miscellaneous transport and binding events

Biological Process

magnesium ion transport
magnesium ion transmembrane transport

Molecular Function

magnesium ion transmembrane transporter activity

Cellular Component

integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000311946
Coding exons: 6
Length: 14699
Individuals with no LoFs: 124632
Homozygous LoFs: 0
Heterozygous LoFs: 21
Defined: 124653
p: 0.0000842

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.21	200	254	0.787	0.0000139	2979
Missense (PolyPhen)		73	96.047	0.76004		1145
Synonymous	1.17	99	115	0.862	0.00000711	1002
Loss of Function	1.89	7	14.9	0.470	7.83e-7	165

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000065	0.000065	rare
Latino/Admixed American	0.00015	0.00014	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00045	0.00045	rare
Finnish	0.000096	0.000093	rare
European (Non-Finnish)	0.000036	0.000035	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Acts as a Mg(2+) transporter. Can also transport other divalent cations such as Ba(2+), Mn(2+), Sr(2+) and Co(2+) but to a much less extent than Mg(2+) (By similarity). May be a receptor for ligands (trioxilins A3 and B3) from the hepoxilin pathway. {ECO:0000250, ECO:0000269|PubMed:15317751}.;

Intolerance Scores

LoFtool: 0.211
RVIS EVS: 0.13
RVIS percentile EVS: 63.49

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.522

Gene Damage Prediction

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