rs146905706

chr6-150394172-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_203395.3(IYD):c.604G>A(p.Ala202Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00234 in 1,614,052 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (6 hom.)
• Consequence: IYD NM_203395.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 0.848

Genes affected

IYD (HGNC:21071): (iodotyrosine deiodinase) 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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0043366253).
• BP6: Variant 6-150394172-G-A is Benign according to our data. Variant chr6-150394172-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 435539.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}. Variant chr6-150394172-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IYD	NM_203395.3	c.604G>A	p.Ala202Thr	missense_variant	4/5	ENST00000344419.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IYD	ENST00000344419.8	c.604G>A	p.Ala202Thr	missense_variant	4/5	1	NM_203395.3	P1

Frequencies

GnomAD3 genomes AF: 0.00183 AC: 278 AN: 152102 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000580

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00273

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.00222 AC: 558 AN: 251434 Hom.: 1 AF XY: 0.00230 AC XY: 313 AN XY: 135886

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00173

Gnomad ASJ exome AF: 0.00546

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.000554

Gnomad NFE exome AF: 0.00359

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00240 AC: 3503 AN: 1461832 Hom.: 6 Cov.: 31 AF XY: 0.00238 AC XY: 1728 AN XY: 727226

Gnomad4 AFR exome AF: 0.000896

Gnomad4 AMR exome AF: 0.00170

Gnomad4 ASJ exome AF: 0.00532

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000232

Gnomad4 FIN exome AF: 0.000880

Gnomad4 NFE exome AF: 0.00266

Gnomad4 OTH exome AF: 0.00250

GnomAD4 genome AF: 0.00180 AC: 274 AN: 152220 Hom.: 0 Cov.: 33 AF XY: 0.00187 AC XY: 139 AN XY: 74418

Gnomad4 AFR AF: 0.000578

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000660

Gnomad4 NFE AF: 0.00273

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.00273 Hom.: 2

Bravo AF: 0.00182

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00244 AC: 21

ExAC AF: 0.00247 AC: 300

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00294

EpiControl AF: 0.00320

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 18, 2021	The c.604G>A (p.A202T) alteration is located in exon 4 (coding exon 4) of the IYD gene. This alteration results from a G to A substitution at nucleotide position 604, causing the alanine (A) at amino acid position 202 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 10, 2017	- -

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2022	- -

IYD-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 11, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	11
Dann	Benign	0.63
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.057	N
LIST_S2	Benign	0.80	T;T;T;T;T;T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.0043	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.1	N;N;N;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.46	N;N;N;N;N;N
REVEL	Benign	0.050
Sift	Benign	0.65	T;T;T;T;T;T
Sift4G	Benign	0.58	T;T;T;T;T;T
Polyphen		0.0010, 0.0	.;B;B;.;.;.
Vest4		0.12
MVP		0.41
MPC		0.059
ClinPred		0.0017	T
GERP RS		-2.2
Varity_R		0.20
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs146905706; hg19: chr6-150715308;