6-150389496-A-G

Position:

• chr6-150389496-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

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. 15/20 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.15

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]

ACMG classification

Verdict is Benign. Variant got -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, 3 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IYD	NM_203395.3	c.323A>G	p.Asn108Ser	missense_variant	2/5	ENST00000344419.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IYD	ENST00000344419.8	c.323A>G	p.Asn108Ser	missense_variant	2/5	1	NM_203395.3	P1

Frequencies

GnomAD3 genomes AF: 0.00959 AC: 1460 AN: 152226 Hom.: 18 Cov.: 33

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

GnomAD3 exomes AF: 0.00299 AC: 751 AN: 251422 Hom.: 6 AF XY: 0.00262 AC XY: 356 AN XY: 135880

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 SAS exome AF: 0.000196

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.: 25 Cov.: 31 AF XY: 0.00165 AC XY: 1198 AN XY: 727208

Gnomad4 AFR exome AF: 0.0324

Gnomad4 AMR exome AF: 0.00411

Gnomad4 ASJ exome AF: 0.00360

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000313

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000678

Gnomad4 OTH exome AF: 0.00382

GnomAD4 genome AF: 0.00966 AC: 1471 AN: 152344 Hom.: 17 Cov.: 33 AF XY: 0.00936 AC XY: 697 AN XY: 74500

Gnomad4 AFR AF: 0.0298

Gnomad4 AMR AF: 0.00869

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000779

Gnomad4 OTH AF: 0.0132

Alfa AF: 0.00286 Hom.: 5

Bravo AF: 0.0112

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.0279 AC: 123

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00321 AC: 390

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.00115

EpiControl AF: 0.00113

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2019

- -

Iodotyrosine deiodination defect Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	12
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	D
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	T
MutationAssessor	Benign	-0.40	N;N;N;.;.;.
MutationTaster	Benign	0.99	N;N;N;N;N;N
PrimateAI	Benign	0.24	T
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	T
GERP RS		3.0
Varity_R		0.11
gMVP		0.084

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

Other links and lift over

dbSNP: rs111758467; hg19: chr6-150710632;