6-150389496-A-G

Variant names:

• chr6-150389496-A-G
• rs111758467
• NM_203395.3:c.323A>G

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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
• Publications: 3 publications found

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

ACMG classification

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 VariationId is 355674.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IYD	NM_203395.3	MANE Select	c.323A>G	p.Asn108Ser	missense	Exon 2 of 5	NP_981932.1	Q6PHW0-1
	IYD	NM_001164694.2		c.323A>G	p.Asn108Ser	missense	Exon 2 of 6	NP_001158166.1	Q6PHW0-4
	IYD	NM_001164695.2		c.323A>G	p.Asn108Ser	missense	Exon 2 of 6	NP_001158167.1	Q6PHW0-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IYD	ENST00000344419.8	TSL:1 MANE Select	c.323A>G	p.Asn108Ser	missense	Exon 2 of 5	ENSP00000343763.4	Q6PHW0-1
	IYD	ENST00000229447.9	TSL:1	c.323A>G	p.Asn108Ser	missense	Exon 2 of 6	ENSP00000229447.5	Q6PHW0-4
	IYD	ENST00000392255.7	TSL:1	c.323A>G	p.Asn108Ser	missense	Exon 2 of 6	ENSP00000376084.3	C9JXJ9

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

GnomAD2 exomes AF: 0.00299 AC: 751 AN: 251422 AF XY: 0.00262

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

African (AFR) AF: 0.0324 AC: 1083 AN: 33472

American (AMR) AF: 0.00411 AC: 184 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00360 AC: 94 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.000313 AC: 27 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.0130 AC: 75 AN: 5768

European-Non Finnish (NFE) AF: 0.000678 AC: 754 AN: 1111974

Other (OTH) AF: 0.00382 AC: 231 AN: 60394

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

African (AFR) AF: 0.0298 AC: 1238 AN: 41580

American (AMR) AF: 0.00869 AC: 133 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000779 AC: 53 AN: 68018

Other (OTH) AF: 0.0132 AC: 28 AN: 2114

Alfa AF: 0.00432 Hom.: 12

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Iodotyrosine deiodination defect (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.50
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.40	N
PhyloP100		3.1
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.060	N
REVEL	Benign	0.056
Sift	Benign	0.77	T
Sift4G	Benign	0.96	T
Polyphen		0.0010	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
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

Other links and lift over

dbSNP: rs111758467; hg19: chr6-150710632;