6-150369121-G-A

Variant names:

• chr6-150369121-G-A
• rs146748197
• NM_203395.3:c.90G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_203395.3(IYD):​c.90G>A​(p.Lys30Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,613,996 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0011 (6 hom.)
• Consequence: IYD NM_203395.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.327
• 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: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 6-150369121-G-A is Benign according to our data. Variant chr6-150369121-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 718813.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.327 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 6 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.90G>A	p.Lys30Lys	synonymous	Exon 1 of 5	NP_981932.1	Q6PHW0-1
	IYD	NM_001164694.2		c.90G>A	p.Lys30Lys	synonymous	Exon 1 of 6	NP_001158166.1	Q6PHW0-4
	IYD	NM_001164695.2		c.90G>A	p.Lys30Lys	synonymous	Exon 1 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.90G>A	p.Lys30Lys	synonymous	Exon 1 of 5	ENSP00000343763.4	Q6PHW0-1
	IYD	ENST00000229447.9	TSL:1	c.90G>A	p.Lys30Lys	synonymous	Exon 1 of 6	ENSP00000229447.5	Q6PHW0-4
	IYD	ENST00000392255.7	TSL:1	c.90G>A	p.Lys30Lys	synonymous	Exon 1 of 6	ENSP00000376084.3	C9JXJ9

Frequencies

GnomAD3 genomes AF: 0.00119 AC: 181 AN: 152012 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00227

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00194

Gnomad OTH AF: 0.000960

GnomAD2 exomes AF: 0.00113 AC: 285 AN: 251230 AF XY: 0.00120

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00222

Gnomad NFE exome AF: 0.00173

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.00111 AC: 1620 AN: 1461866 Hom.: 6 Cov.: 31 AF XY: 0.00111 AC XY: 809 AN XY: 727236

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.000447 AC: 20 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000536 AC: 14 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000661 AC: 57 AN: 86256

European-Finnish (FIN) AF: 0.00212 AC: 113 AN: 53416

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5764

European-Non Finnish (NFE) AF: 0.00123 AC: 1368 AN: 1111996

Other (OTH) AF: 0.000729 AC: 44 AN: 60396

GnomAD4 genome AF: 0.00119 AC: 181 AN: 152130 Hom.: 1 Cov.: 31 AF XY: 0.00120 AC XY: 89 AN XY: 74366

African (AFR) AF: 0.0000723 AC: 3 AN: 41520

American (AMR) AF: 0.000785 AC: 12 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4816

European-Finnish (FIN) AF: 0.00227 AC: 24 AN: 10578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00194 AC: 132 AN: 68000

Other (OTH) AF: 0.000950 AC: 2 AN: 2106

Alfa AF: 0.00166 Hom.: 1

Bravo AF: 0.000941

EpiCase AF: 0.00196

EpiControl AF: 0.00130

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.0
DANN	Benign	0.61
PhyloP100		0.33
PromoterAI		-0.091	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs146748197; hg19: chr6-150690257; COSMIC: COSV57599373; COSMIC: COSV57599373;