chr3-24143542-T-TGGTCGCCACATGGGCTTC

Variant names:

• chr3-24143542-T-TGGTCGCCACATGGGCTTC
• rs1553616532
• NM_001354712.2:c.679_696dupGAAGCCCATGTGGCGACC

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4

The NM_001354712.2(THRB):​c.679_696dupGAAGCCCATGTGGCGACC​(p.Thr232_Asn233insGluAlaHisValAlaThr) variant causes a conservative inframe insertion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: THRB NM_001354712.2 conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 4.00

Genes affected

THRB (HGNC:11799): (thyroid hormone receptor beta) 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. Mutations in this gene are known to be a cause of generalized thyroid hormone resistance (GTHR), a syndrome characterized by goiter and high levels of circulating thyroid hormone (T3-T4), with normal or slightly elevated thyroid stimulating hormone (TSH). Several alternatively spliced transcript variants encoding the same protein have been observed for this gene. [provided by RefSeq, Jul 2008]

ENSG00000289130 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001354712.2.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THRB	NM_001354712.2	c.679_696dupGAAGCCCATGTGGCGACC	p.Thr232_Asn233insGluAlaHisValAlaThr	conservative_inframe_insertion	Exon 8 of 11	ENST00000646209.2	NP_001341641.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THRB	ENST00000646209.2	c.679_696dupGAAGCCCATGTGGCGACC	p.Thr232_Asn233insGluAlaHisValAlaThr	conservative_inframe_insertion	Exon 8 of 11		NM_001354712.2	ENSP00000496686.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 03, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: THRB c.679_696dup18 (p.Glu227_Thr232dup) results in an in-frame duplication that is predicted to duplicate 6 amino acids into the encoded protein. The variant was absent in 251040 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.679_696dup18 in individuals affected with Thyroid Hormone Resistance, Generalized, Autosomal Dominant and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 492909). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Thyroid hormone resistance, generalized, autosomal dominant Uncertain:1

Feb 21, 2012

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553616532; hg19: chr3-24185033;