NM_001354712.2:c.*4988T>C

Variant names:

• chr3-24117896-A-G
• rs1349265
• NM_001354712.2:c.*4988T>C

Variant summary

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

The NM_001354712.2(THRB):​c.*4988T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.531 in 152,144 control chromosomes in the GnomAD database, including 24,969 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (24969 hom., cov: 33)
  • Exomes 𝑓: 0.50 (0 hom.)
• Consequence: THRB NM_001354712.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.21
• Publications: 14 publications found

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]

THRB Gene-Disease associations (from GenCC):

• thyroid hormone resistance, generalized, autosomal dominant

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• resistance to thyroid hormone due to a mutation in thyroid hormone receptor beta

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• thyroid hormone resistance, generalized, autosomal recessive

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 3-24117896-A-G is Benign according to our data. Variant chr3-24117896-A-G is described in ClinVar as [Benign]. Clinvar id is 344545.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.69 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THRB	NM_001354712.2	c.*4988T>C		3_prime_UTR_variant	Exon 11 of 11	ENST00000646209.2	NP_001341641.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THRB	ENST00000646209.2	c.*4988T>C		3_prime_UTR_variant	Exon 11 of 11		NM_001354712.2	ENSP00000496686.2
THRB	ENST00000396671.7	c.*4988T>C		3_prime_UTR_variant	Exon 10 of 10	5		ENSP00000379904.2

Frequencies

GnomAD3 genomes AF: 0.531 AC: 80756 AN: 152024 Hom.: 24971 Cov.: 33

Gnomad AFR AF: 0.193

Gnomad AMI AF: 0.802

Gnomad AMR AF: 0.525

Gnomad ASJ AF: 0.636

Gnomad EAS AF: 0.685

Gnomad SAS AF: 0.554

Gnomad FIN AF: 0.659

Gnomad MID AF: 0.595

Gnomad NFE AF: 0.695

Gnomad OTH AF: 0.564

GnomAD4 exome AF: 0.500 AC: 1 AN: 2 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.500 AC: 1 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.531 AC: 80770 AN: 152142 Hom.: 24969 Cov.: 33 AF XY: 0.531 AC XY: 39499 AN XY: 74376

African (AFR) AF: 0.192 AC: 7990 AN: 41514

American (AMR) AF: 0.525 AC: 8026 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.636 AC: 2206 AN: 3468

East Asian (EAS) AF: 0.684 AC: 3544 AN: 5178

South Asian (SAS) AF: 0.554 AC: 2674 AN: 4824

European-Finnish (FIN) AF: 0.659 AC: 6969 AN: 10582

Middle Eastern (MID) AF: 0.602 AC: 177 AN: 294

European-Non Finnish (NFE) AF: 0.695 AC: 47257 AN: 67976

Other (OTH) AF: 0.567 AC: 1197 AN: 2112

Alfa AF: 0.648 Hom.: 63313

Bravo AF: 0.509

Asia WGS AF: 0.560 AC: 1949 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Thyroid hormone resistance, generalized, autosomal dominant Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.2
DANN	Benign	0.60
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

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: rs1349265; hg19: chr3-24159387;