NM_203395.3:c.181G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_203395.3(IYD):c.181G>A(p.Ala61Thr) variant causes a missense, 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. 15/21 in silico tools predict 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_203395.3 missense, splice_region

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.71

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

thyroid dyshormonogenesis 4
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
familial thyroid dyshormonogenesis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

IYD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006178409).

BP6

Variant 6-150389354-G-A is Benign according to our data. Variant chr6-150389354-G-A is described in ClinVar as Benign. ClinVar VariationId is 716756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 28 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_203395.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IYD	NM_203395.3	MANE Select	c.181G>A	p.Ala61Thr	missense splice_region	Exon 2 of 5	NP_981932.1	Q6PHW0-1
IYD	NM_001164694.2		c.181G>A	p.Ala61Thr	missense splice_region	Exon 2 of 6	NP_001158166.1	Q6PHW0-4
IYD	NM_001164695.2		c.181G>A	p.Ala61Thr	missense splice_region	Exon 2 of 6	NP_001158167.1	Q6PHW0-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IYD	ENST00000344419.8	TSL:1 MANE Select	c.181G>A	p.Ala61Thr	missense splice_region	Exon 2 of 5	ENSP00000343763.4	Q6PHW0-1
IYD	ENST00000229447.9	TSL:1	c.181G>A	p.Ala61Thr	missense splice_region	Exon 2 of 6	ENSP00000229447.5	Q6PHW0-4
IYD	ENST00000392255.7	TSL:1	c.181G>A	p.Ala61Thr	missense splice_region	Exon 2 of 6	ENSP00000376084.3	C9JXJ9

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

GnomAD2 exomes

AF:

0.00285

AC:

716

AN:

251152

AF XY:

0.00339

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 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

African (AFR)

AF:

0.000180

AC:

AN:

33418

American (AMR)

AF:

0.000716

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00486

AC:

127

AN:

26116

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39668

South Asian (SAS)

AF:

0.0127

AC:

1092

AN:

86174

European-Finnish (FIN)

AF:

0.00336

AC:

179

AN:

53350

Middle Eastern (MID)

AF:

0.00850

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00124

AC:

1374

AN:

1110178

Other (OTH)

AF:

0.00254

AC:

153

AN:

60308

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

139

278

417

556

695

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

156

208

260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00175

AC:

267

AN:

152290

Hom.:

Cov.:

AF XY:

0.00212

AC XY:

158

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.000192

AC:

AN:

41564

American (AMR)

AF:

0.00144

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5186

South Asian (SAS)

AF:

0.0158

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00198

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0137

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00165

AC:

112

AN:

68028

Other (OTH)

AF:

0.00284

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00185

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

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.022

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.091

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.52

MetaRNN

Benign

0.0053

MetaSVM

Benign

-0.76

MutationAssessor

Benign

1.6

PhyloP100

2.7

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.020

REVEL

Benign

0.14

Sift

Benign

0.58

Sift4G

Benign

0.58

Polyphen

0.0010

Vest4

0.19

MVP

0.88

MPC

0.059

ClinPred

0.013

GERP RS

4.5

Varity_R

0.041

gMVP

0.23

Mutation Taster

=94/6

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over