17-40093323-T-TC

Variant names:

• chr17-40093323-T-TC
• ENST00000264637.8:c.1416dupC

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_003250.6(THRA):​c.1416dupC​(p.Ser473LeufsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: THRA NM_003250.6 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.0490

Genes affected

THRA (HGNC:11796): (thyroid hormone receptor alpha) The protein encoded by this gene is a nuclear hormone receptor for triiodothyronine. It is one of the several receptors for thyroid hormone, and has been shown to mediate the biological activities of thyroid hormone. Knockout studies in mice suggest that the different receptors, while having certain extent of redundancy, may mediate different functions of thyroid hormone. Alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]

NR1D1 (HGNC:7962): (nuclear receptor subfamily 1 group D member 1) This gene encodes a transcription factor that is a member of the nuclear receptor subfamily 1. The encoded protein is a ligand-sensitive transcription factor that negatively regulates the expression of core clock proteins. In particular this protein represses the circadian clock transcription factor aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL). This protein may also be involved in regulating genes that function in metabolic, inflammatory and cardiovascular processes. [provided by RefSeq, Jan 2013]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.038 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-40093323-T-TC is Pathogenic according to our data. Variant chr17-40093323-T-TC is described in ClinVar as [Pathogenic]. Clinvar id is 1299533.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR1D1	NM_021724.5	c.1646-42dupG		intron_variant	Intron 7 of 7	ENST00000246672.4	NP_068370.1
THRA	NM_001190919.2	c.1416dupC	p.Ser473LeufsTer2	frameshift_variant	Exon 10 of 10		NP_001177848.1
THRA	NM_003250.6	c.1416dupC	p.Ser473LeufsTer2	frameshift_variant	Exon 10 of 10		NP_003241.2
THRA	NM_001190918.2	c.1299dupC	p.Ser434LeufsTer2	frameshift_variant	Exon 10 of 10		NP_001177847.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THRA	ENST00000264637.8	c.1416dupC	p.Ser473LeufsTer2	frameshift_variant	Exon 10 of 10	1		ENSP00000264637.4
THRA	ENST00000584985.5	c.1299dupC	p.Ser434LeufsTer2	frameshift_variant	Exon 10 of 10	1		ENSP00000463466.1
NR1D1	ENST00000246672.4	c.1646-42dupG		intron_variant	Intron 7 of 7	1	NM_021724.5	ENSP00000246672.3
THRA	ENST00000394121.8	c.1416dupC	p.Ser473LeufsTer2	frameshift_variant	Exon 10 of 10	2		ENSP00000377679.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital nongoitrous hypothyroidism 6 Pathogenic:1

Oct 01, 2021

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PM2, PP3, PP4 -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-38249576;