6-150395560-T-C

Variant names:

• chr6-150395560-T-C
• rs612421
• ENST00000229447.9:c.793T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001164694.2(IYD):​c.793T>C​(p.Cys265Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.907 in 1,537,026 control chromosomes in the GnomAD database, including 633,605 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C265Y) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.91 (63206 hom., cov: 33)
  • Exomes 𝑓: 0.91 (570399 hom.)
• Consequence: IYD NM_001164694.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.97
• Publications: 24 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.011365E-7).
• BP6: Variant 6-150395560-T-C is Benign according to our data. Variant chr6-150395560-T-C is described in ClinVar as Benign. ClinVar VariationId is 257584.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.95 is higher than 0.05.

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.687+1305T>C		intron	N/A	NP_981932.1
	IYD	NM_001164694.2		c.793T>C	p.Cys265Arg	missense	Exon 5 of 6	NP_001158166.1
	IYD	NM_001164695.2		c.*4+106T>C		intron	N/A	NP_001158167.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IYD	ENST00000229447.9	TSL:1	c.793T>C	p.Cys265Arg	missense	Exon 5 of 6	ENSP00000229447.5
	IYD	ENST00000392255.7	TSL:1	c.793T>C	p.Cys265Arg	missense	Exon 5 of 6	ENSP00000376084.3
	IYD	ENST00000344419.8	TSL:1 MANE Select	c.687+1305T>C		intron	N/A	ENSP00000343763.4

Frequencies

GnomAD3 genomes AF: 0.910 AC: 138502 AN: 152180 Hom.: 63160 Cov.: 33

Gnomad AFR AF: 0.958

Gnomad AMI AF: 0.909

Gnomad AMR AF: 0.866

Gnomad ASJ AF: 0.854

Gnomad EAS AF: 0.794

Gnomad SAS AF: 0.808

Gnomad FIN AF: 0.871

Gnomad MID AF: 0.899

Gnomad NFE AF: 0.916

Gnomad OTH AF: 0.904

GnomAD2 exomes AF: 0.878 AC: 126813 AN: 144376 AF XY: 0.873

Gnomad AFR exome AF: 0.964

Gnomad AMR exome AF: 0.867

Gnomad ASJ exome AF: 0.857

Gnomad EAS exome AF: 0.798

Gnomad FIN exome AF: 0.869

Gnomad NFE exome AF: 0.918

Gnomad OTH exome AF: 0.894

GnomAD4 exome AF: 0.907 AC: 1255419 AN: 1384728 Hom.: 570399 Cov.: 47 AF XY: 0.903 AC XY: 617049 AN XY: 683316

African (AFR) AF: 0.961 AC: 30355 AN: 31592

American (AMR) AF: 0.866 AC: 30911 AN: 35700

Ashkenazi Jewish (ASJ) AF: 0.860 AC: 21662 AN: 25180

East Asian (EAS) AF: 0.770 AC: 27519 AN: 35734

South Asian (SAS) AF: 0.806 AC: 63852 AN: 79228

European-Finnish (FIN) AF: 0.869 AC: 30431 AN: 35008

Middle Eastern (MID) AF: 0.893 AC: 5085 AN: 5694

European-Non Finnish (NFE) AF: 0.921 AC: 993592 AN: 1078680

Other (OTH) AF: 0.898 AC: 52012 AN: 57912

GnomAD4 genome AF: 0.910 AC: 138605 AN: 152298 Hom.: 63206 Cov.: 33 AF XY: 0.903 AC XY: 67274 AN XY: 74466

African (AFR) AF: 0.958 AC: 39808 AN: 41558

American (AMR) AF: 0.866 AC: 13259 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.854 AC: 2964 AN: 3470

East Asian (EAS) AF: 0.795 AC: 4113 AN: 5174

South Asian (SAS) AF: 0.808 AC: 3899 AN: 4824

European-Finnish (FIN) AF: 0.871 AC: 9243 AN: 10618

Middle Eastern (MID) AF: 0.888 AC: 261 AN: 294

European-Non Finnish (NFE) AF: 0.916 AC: 62316 AN: 68026

Other (OTH) AF: 0.904 AC: 1913 AN: 2116

Alfa AF: 0.909 Hom.: 116964

Bravo AF: 0.915

TwinsUK AF: 0.929 AC: 3443

ALSPAC AF: 0.917 AC: 3534

ESP6500AA AF: 0.956 AC: 1323

ESP6500EA AF: 0.906 AC: 2882

ExAC AF: 0.857 AC: 18713

Asia WGS AF: 0.808 AC: 2811 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Iodotyrosine deiodination defect (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.14
DANN	Benign	0.26
DEOGEN2	Benign	0.013	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.26	T
MetaRNN	Benign	9.0e-7	T
MetaSVM	Benign	-0.89	T
PhyloP100		-3.0
PrimateAI	Benign	0.26	T
PROVEAN	Benign	1.5	N
REVEL	Benign	0.17
Sift	Benign	0.43	T
Sift4G	Benign	0.36	T
Vest4		0.13
MPC		0.10
ClinPred		0.0030	T
GERP RS		-6.1
gMVP		0.75
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs612421; hg19: chr6-150716696; COSMIC: COSV107213338; COSMIC: COSV107213338;