IYD

protein-coding

iodotyrosine deiodinase

Gene summary

This gene encodes an enzyme that catalyzes the oxidative NADPH-dependent deiodination of mono- and diiodotyrosine, which are the halogenated byproducts of thyroid hormone production. The N-terminus of the protein functions as a membrane anchor. Mutations in this gene cause congenital hypothyroidism due to dyshormonogenesis type 4, which is also referred to as deiodinase deficiency, or iodotyrosine dehalogenase deficiency, or thyroid hormonogenesis type 4. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

Previous symbols:

C6orf71

MANE transcript

NM_203395.3

Inheritance

ClinVar variants

P:9U:48B:23

Top phenotype

Thyroid dyshormonogenesis 4

gnomAD constraint

pLI —, LoF o/e 0.45

Max pathogenic AF

—

Genomic locus

chr6:150,368,892-150,405,969

External References & Databases

Ensembl (ENSG00000009765)

Transcript & Mutation Effects

hg38 • Region Span ~37.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

thyroid dyshormonogenesis 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010136

Submitter: Labcorp Genetics (formerly Invitae)

familial thyroid dyshormonogenesisSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010132

Submitter: Orphanet

thyroid dyshormonogenesis 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010136

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Thyroid dyshormonogenesis 4AR

Manifestation: Endocrine

Intervention: Endocrine

Rationale: Individuals may present with clinical signs and sequelae of childhood hypothyroidism, which can lead to long-term neurologic and other effects, and medical treatment of hypothyroidism (eg, with T4) can be beneficial

Comments: In heterozygotes, clinical hypothyroidism has been described as arising at a later age than in individuals with biallelic variants

Refs: 18765512; 18434651; 22535972

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to IYD variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 56

not providedTotal: 28

IYD-related disorderTotal: 15

Iodotyrosine deiodination defectTotal: 11

Type 2 diabetes mellitusTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_203395.3. 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				14 clinvar		14
missense		4 clinvar	47 clinvar	6 clinvar	3 clinvar	60
nonsense		1 clinvar				1
start loss						0
frameshift		4 clinvar				4
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	0	9	48	20	3	80

Highest pathogenic variant AF is 0.00024969393

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 24 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_203395.3	RefSeq	NP_981932.1	5	MANE Select
ENST00000344419.8	Ensembl	ENSP00000343763.4	5	MANE Select
NM_001164694.2	RefSeq	NP_001158166.1	6	Standard
NM_001164695.2	RefSeq	NP_001158167.1	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Thyroid hormone synthesis - Homo sapiens (human)
Metabolism of amino acids and derivatives
Metabolism
Thyroxine biosynthesis
Amine-derived hormones

Biological Process

tyrosine metabolic process
thyroid hormone generation
thyroid hormone metabolic process
oxidation-reduction process
cellular oxidant detoxification

Molecular Function

iodide peroxidase activity
protein binding
FMN binding
oxidoreductase activity

Cellular Component

nucleoplasm
plasma membrane
integral component of plasma membrane
cytoplasmic vesicle membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000229447
Coding exons: 6
Length: 37078
Individuals with no LoFs: 125726
Homozygous LoFs: 0
Heterozygous LoFs: 22
Defined: 125748
p: 0.0000875

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.243	153	162	0.946	0.00000897	1948
Missense (PolyPhen)		39	44.577	0.87489		558
Synonymous	0.313	56	59.1	0.948	0.00000356	525
Loss of Function	1.87	6	13.4	0.448	6.39e-7	163

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00014	0.00014	rare
South Asian	0.000033	0.000033	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the oxidative NADPH-dependent deiodination of monoiodotyrosine (L-MIT) or diiodotyrosine (L-DIT) (PubMed:15289438, PubMed:25395621, PubMed:18434651). Acts during the hydrolysis of thyroglobulin to liberate iodide, which can then reenter the hormone-producing pathways (PubMed:18434651). Acts more efficiently on monoiodotyrosine than on diiodotyrosine (PubMed:15289438). {ECO:0000269|PubMed:15289438, ECO:0000269|PubMed:18434651, ECO:0000269|PubMed:25395621}.;

Recessive Scores

pRec: 0.167

Intolerance Scores

LoFtool: 0.287
RVIS EVS: 2
RVIS percentile EVS: 97.66

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.0193

Gene Damage Prediction

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