6-150395560-T-C

Position:

• chr6-150395560-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001164694.2(IYD):​c.793T>C​(p.Cys265Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.907 in 1,537,026 control chromosomes in the GnomAD database, including 633,605 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C265Y) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.91 (63206 hom., cov: 33)
  • Exomes 𝑓: 0.91 (570399 hom.)
• Consequence: IYD NM_001164694.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.97

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.011365E-7).
• BP6: Variant 6-150395560-T-C is Benign according to our data. Variant chr6-150395560-T-C is described in ClinVar as [Benign]. Clinvar id is 257584.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-150395560-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.95 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IYD	NM_203395.3	c.687+1305T>C		intron_variant		ENST00000344419.8	NP_981932.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IYD	ENST00000344419.8	c.687+1305T>C		intron_variant		1	NM_203395.3	ENSP00000343763.4

Frequencies

GnomAD3 genomes AF: 0.910 AC: 138502 AN: 152180 Hom.: 63160 Cov.: 33

Gnomad AFR AF: 0.958

Gnomad AMI AF: 0.909

Gnomad AMR AF: 0.866

Gnomad ASJ AF: 0.854

Gnomad EAS AF: 0.794

Gnomad SAS AF: 0.808

Gnomad FIN AF: 0.871

Gnomad MID AF: 0.899

Gnomad NFE AF: 0.916

Gnomad OTH AF: 0.904

GnomAD3 exomes AF: 0.878 AC: 126813 AN: 144376 Hom.: 55932 AF XY: 0.873 AC XY: 67322 AN XY: 77094

Gnomad AFR exome AF: 0.964

Gnomad AMR exome AF: 0.867

Gnomad ASJ exome AF: 0.857

Gnomad EAS exome AF: 0.798

Gnomad SAS exome AF: 0.805

Gnomad FIN exome AF: 0.869

Gnomad NFE exome AF: 0.918

Gnomad OTH exome AF: 0.894

GnomAD4 exome AF: 0.907 AC: 1255419 AN: 1384728 Hom.: 570399 Cov.: 47 AF XY: 0.903 AC XY: 617049 AN XY: 683316

Gnomad4 AFR exome AF: 0.961

Gnomad4 AMR exome AF: 0.866

Gnomad4 ASJ exome AF: 0.860

Gnomad4 EAS exome AF: 0.770

Gnomad4 SAS exome AF: 0.806

Gnomad4 FIN exome AF: 0.869

Gnomad4 NFE exome AF: 0.921

Gnomad4 OTH exome AF: 0.898

GnomAD4 genome AF: 0.910 AC: 138605 AN: 152298 Hom.: 63206 Cov.: 33 AF XY: 0.903 AC XY: 67274 AN XY: 74466

Gnomad4 AFR AF: 0.958

Gnomad4 AMR AF: 0.866

Gnomad4 ASJ AF: 0.854

Gnomad4 EAS AF: 0.795

Gnomad4 SAS AF: 0.808

Gnomad4 FIN AF: 0.871

Gnomad4 NFE AF: 0.916

Gnomad4 OTH AF: 0.904

Alfa AF: 0.907 Hom.: 72984

Bravo AF: 0.915

TwinsUK AF: 0.929 AC: 3443

ALSPAC AF: 0.917 AC: 3534

ESP6500AA AF: 0.956 AC: 1323

ESP6500EA AF: 0.906 AC: 2882

ExAC AF: 0.857 AC: 18713

Asia WGS AF: 0.808 AC: 2811 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2021

- -

Iodotyrosine deiodination defect Benign:1

Benign, no assertion criteria provided

clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.14
DANN	Benign	0.26
DEOGEN2	Benign	0.013	.;.;T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.26	T;T;T
MetaRNN	Benign	9.0e-7	T;T;T
MetaSVM	Benign	-0.89	T
PrimateAI	Benign	0.26	T
PROVEAN	Benign	1.5	N;N;N
REVEL	Benign	0.17
Sift	Benign	0.43	T;T;T
Sift4G	Benign	0.36	T;T;T
Vest4		0.13
MPC		0.10
ClinPred		0.0030	T
GERP RS		-6.1
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs612421; hg19: chr6-150716696;