Genetic Variant IYD:p.Ala61Thr (chr6-150389354-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_StrongBS2

The NM_001318495.2(IYD):c.3G>A(p.Met1?) variant causes a start lost, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00204 in 1,611,986 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0018 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0021 ( 28 hom. )

Consequence

IYD
NM_001318495.2 start_lost, splice_region

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.71

Variant links:

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]

IYD links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP6

Variant 6-150389354-G-A is Benign according to our data. Variant chr6-150389354-G-A is described in ClinVar as [Benign]. Clinvar id is 716756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-150389354-G-A is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IYD	NM_203395.3 link	c.181G>A	p.Ala61Thr	missense_variant, splice_region_variant	Exon 2 of 5	ENST00000344419.8	NP_981932.1	Q6PHW0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IYD	ENST00000344419.8 link	c.181G>A	p.Ala61Thr	missense_variant, splice_region_variant	Exon 2 of 5	1	NM_203395.3	ENSP00000343763.4		Q6PHW0-1

Frequencies

GnomAD3 genomes

AF:

0.00175

AC:

266

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0156

Gnomad FIN

AF:

0.00198

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00165

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00285

AC:

716

AN:

251152

Hom.:

AF XY:

0.00339

AC XY:

460

AN XY:

135750

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000636

Gnomad ASJ exome

AF:

0.00447

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.0127

Gnomad FIN exome

AF:

0.00329

Gnomad NFE exome

AF:

0.00144

Gnomad OTH exome

AF:

0.00327

GnomAD4 exome

AF:

0.00206

AC:

3014

AN:

1459696

Hom.:

Cov.:

AF XY:

0.00243

AC XY:

1765

AN XY:

726364

show subpopulations

Gnomad4 AFR exome

AF:

0.000180

Gnomad4 AMR exome

AF:

0.000716

Gnomad4 ASJ exome

AF:

0.00486

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0127

Gnomad4 FIN exome

AF:

0.00336

Gnomad4 NFE exome

AF:

0.00124

Gnomad4 OTH exome

AF:

0.00254

GnomAD4 genome

AF:

0.00175

AC:

267

AN:

152290

Hom.:

Cov.:

AF XY:

0.00212

AC XY:

158

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.000192

Gnomad4 AMR

AF:

0.00144

Gnomad4 ASJ

AF:

0.00461

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.0158

Gnomad4 FIN

AF:

0.00198

Gnomad4 NFE

AF:

0.00165

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00180

Hom.:

Bravo

AF:

0.000948

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00186

AC:

ExAC

AF:

0.00288

AC:

350

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.00202

EpiControl

AF:

0.00160

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jul 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

IYD: BP4, BS1, BS2 -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.022

.;T;.;.;T;T

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.091

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.52

T;T;T;T;T;T

MetaRNN

Benign

0.0053

T;T;T;T;T;T

MetaSVM

Benign

-0.76

MutationAssessor

Benign

1.6

L;L;L;.;.;.

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.020

N;N;N;N;N;N

REVEL

Benign

0.14

Sift

Benign

0.58

T;T;T;T;T;T

Sift4G

Benign

0.58

T;T;T;T;T;T

Polyphen

0.0010, 0.0020

.;B;B;.;.;.

Vest4

0.19

MVP

0.88

MPC

0.059

ClinPred

0.013

GERP RS

4.5

Varity_R

0.041

gMVP

0.23

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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