rs863223276

Variant names:

• chr6-150389486-TTCA-T
• rs863223276
• NM_203395.3:c.315_317delCAT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM4_Supporting PP5

The NM_001164694.2(IYD):​c.315_317delCAT​(p.Phe105_Ile106delinsLeu) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00025 in 1,613,976 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: IYD NM_001164694.2 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 3.35
• Publications: 1 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: Uncertain_significance. The variant received 2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001164694.2. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 6-150389486-TTCA-T is Pathogenic according to our data. Variant chr6-150389486-TTCA-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 738.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164694.2. 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.315_317delCAT	p.Phe105_Ile106delinsLeu	disruptive_inframe_deletion	Exon 2 of 5	NP_981932.1
	IYD	NM_001164694.2		c.315_317delCAT	p.Phe105_Ile106delinsLeu	disruptive_inframe_deletion	Exon 2 of 6	NP_001158166.1
	IYD	NM_001164695.2		c.315_317delCAT	p.Phe105_Ile106delinsLeu	disruptive_inframe_deletion	Exon 2 of 6	NP_001158167.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IYD	ENST00000344419.8	TSL:1 MANE Select	c.315_317delCAT	p.Phe105_Ile106delinsLeu	disruptive_inframe_deletion	Exon 2 of 5	ENSP00000343763.4
	IYD	ENST00000229447.9	TSL:1	c.315_317delCAT	p.Phe105_Ile106delinsLeu	disruptive_inframe_deletion	Exon 2 of 6	ENSP00000229447.5
	IYD	ENST00000392255.7	TSL:1	c.315_317delCAT	p.Phe105_Ile106delinsLeu	disruptive_inframe_deletion	Exon 2 of 6	ENSP00000376084.3

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000103 AC: 26 AN: 251400 AF XY: 0.000110

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000229

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000259 AC: 379 AN: 1461798 Hom.: 0 AF XY: 0.000249 AC XY: 181 AN XY: 727204

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000326 AC: 362 AN: 1111970

Other (OTH) AF: 0.000248 AC: 15 AN: 60394

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10 AN XY: 74338

African (AFR) AF: 0.0000724 AC: 3 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 68026

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000155

EpiCase AF: 0.000491

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	-	-	Iodotyrosine deiodination defect (2)
1	-	-	IYD-related disorder (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.3
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.40		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.40		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs863223276; hg19: chr6-150710622;