6-150389496-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_203395.3(IYD):c.323A>G(p.Asn108Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00243 in 1,614,146 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0097 ( 17 hom., cov: 33)

Exomes 𝑓: 0.0017 ( 25 hom. )

Consequence

IYD
NM_203395.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.15

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_203395.3

BP4

Computational evidence support a benign effect (MetaRNN=0.004104018).

BP6

Variant 6-150389496-A-G is Benign according to our data. Variant chr6-150389496-A-G is described in ClinVar as [Benign]. Clinvar id is 355674.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-150389496-A-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00966 (1471/152344) while in subpopulation AFR AF = 0.0298 (1238/41580). AF 95% confidence interval is 0.0284. There are 17 homozygotes in GnomAd4. There are 697 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position FAILED quality control check.

BS2

High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IYD	NM_203395.3 link	c.323A>G	p.Asn108Ser	missense_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.323A>G	p.Asn108Ser	missense_variant	Exon 2 of 5	1	NM_203395.3	ENSP00000343763.4		Q6PHW0-1

Frequencies

GnomAD3 genomes

AF:

0.00959

AC:

1460

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0295

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00870

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.000779

Gnomad OTH

AF:

0.0134

GnomAD2 exomes

AF:

0.00299

AC:

751

AN:

251422

AF XY:

0.00262

show subpopulations

Gnomad AFR exome

AF:

0.0286

Gnomad AMR exome

AF:

0.00347

Gnomad ASJ exome

AF:

0.00357

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000915

Gnomad OTH exome

AF:

0.00326

GnomAD4 exome

AF:

0.00167

AC:

2448

AN:

1461802

Hom.:

Cov.:

AF XY:

0.00165

AC XY:

1198

AN XY:

727208

show subpopulations

Gnomad4 AFR exome

AF:

0.0324

AC:

1083

AN:

33472

Gnomad4 AMR exome

AF:

0.00411

AC:

184

AN:

44720

Gnomad4 ASJ exome

AF:

0.00360

AC:

AN:

26128

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39680

Gnomad4 SAS exome

AF:

0.000313

AC:

AN:

86256

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

53410

Gnomad4 NFE exome

AF:

0.000678

AC:

754

AN:

1111974

Gnomad4 Remaining exome

AF:

0.00382

AC:

231

AN:

60394

Heterozygous variant carriers

132

264

396

528

660

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

100

150

200

250

<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:

0.00966

AC:

1471

AN:

152344

Hom.:

Cov.:

AF XY:

0.00936

AC XY:

697

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.0298

AC:

0.0297739

AN:

0.0297739

Gnomad4 AMR

AF:

0.00869

AC:

0.00868713

AN:

0.00868713

Gnomad4 ASJ

AF:

0.00346

AC:

0.00345622

AN:

0.00345622

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.000414

AC:

0.000414079

AN:

0.000414079

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.000779

AC:

0.000779206

AN:

0.000779206

Gnomad4 OTH

AF:

0.0132

AC:

0.013245

AN:

0.013245

Heterozygous variant carriers

140

209

279

349

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00432

Hom.:

Bravo

AF:

0.0112

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.0279

AC:

123

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00321

AC:

390

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.00115

EpiControl

AF:

0.00113

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Iodotyrosine deiodination defect

Benign:1

May 04, 2022

Fulgent Genetics, Fulgent Genetics

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

0.051

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Benign

0.61

DEOGEN2

Benign

0.061

.;T;.;.;T;T

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.50

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.88

D;D;D;D;D;D

MetaRNN

Benign

0.0041

T;T;T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.40

N;N;N;.;.;.

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.060

N;N;N;N;N;N

REVEL

Benign

0.056

Sift

Benign

0.77

T;T;T;T;T;T

Sift4G

Benign

0.96

T;T;T;T;T;T

Polyphen

0.0010, 0.0070

.;B;B;.;.;.

Vest4

0.19

MVP

0.65

MPC

0.052

ClinPred

0.0020

GERP RS

3.0

Varity_R

0.11

gMVP

0.084

Mutation Taster

=100/0

polymorphism

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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