6-150389354-G-A

Position:

• chr6-150389354-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.71

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 -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/exons	MANE	Protein	UniProt
IYD	NM_203395.3	c.181G>A	p.Ala61Thr	missense_variant, splice_region_variant	2/5	ENST00000344419.8	NP_981932.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IYD	ENST00000344419.8	c.181G>A	p.Ala61Thr	missense_variant, splice_region_variant	2/5	1	NM_203395.3	ENSP00000343763.4

Frequencies

GnomAD3 genomes AF: 0.00175 AC: 266 AN: 152174 Hom.: 1 Cov.: 32

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.: 8 AF XY: 0.00339 AC XY: 460 AN XY: 135750

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.: 28 Cov.: 30 AF XY: 0.00243 AC XY: 1765 AN XY: 726364

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.: 1 Cov.: 32 AF XY: 0.00212 AC XY: 158 AN XY: 74458

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.: 0

Bravo AF: 0.000948

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00288 AC: 350

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.00202

EpiControl AF: 0.00160

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	IYD: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	17
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	D
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	T
MutationAssessor	Benign	1.6	L;L;L;.;.;.
PrimateAI	Benign	0.24	T
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	T
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

Other links and lift over

dbSNP: rs144193430; hg19: chr6-150710490;