chr6-150389462-CTCAATAAGAGACGG-C

Variant names:

• chr6-150389462-CTCAATAAGAGACGG-C
• NM_203395.3:c.293_306delATAAGAGACGGTCA

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_001318495.2(IYD):​c.115_124+4delATAAGAGACGGTCA​(p.Ile39AsnfsTer30) variant causes a frameshift, splice donor, splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IYD NM_001318495.2 frameshift, splice_donor, splice_region, intron
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.64
• Publications: 0 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 6-150389462-CTCAATAAGAGACGG-C is Pathogenic according to our data. Variant chr6-150389462-CTCAATAAGAGACGG-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3593218.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001318495.2. 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.293_306delATAAGAGACGGTCA	p.Asn98SerfsTer6	frameshift	Exon 2 of 5	NP_981932.1	Q6PHW0-1
	IYD	NM_001164694.2		c.293_306delATAAGAGACGGTCA	p.Asn98SerfsTer6	frameshift	Exon 2 of 6	NP_001158166.1	Q6PHW0-4
	IYD	NM_001164695.2		c.293_306delATAAGAGACGGTCA	p.Asn98SerfsTer6	frameshift	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.293_306delATAAGAGACGGTCA	p.Asn98SerfsTer6	frameshift	Exon 2 of 5	ENSP00000343763.4	Q6PHW0-1
	IYD	ENST00000229447.9	TSL:1	c.293_306delATAAGAGACGGTCA	p.Asn98SerfsTer6	frameshift	Exon 2 of 6	ENSP00000229447.5	Q6PHW0-4
	IYD	ENST00000392255.7	TSL:1	c.293_306delATAAGAGACGGTCA	p.Asn98SerfsTer6	frameshift	Exon 2 of 6	ENSP00000376084.3	C9JXJ9

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Iodotyrosine deiodination defect (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.6

Splicing

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

Other links and lift over

hg19: chr6-150710598;