rs13081063

chr3-24123019-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001354712.2(THRB):c.1251T>C(p.Phe417=) variant causes a synonymous change. The variant allele was found at a frequency of 0.032 in 1,614,182 control chromosomes in the GnomAD database, including 1,020 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (80 hom., cov: 32)
  • Exomes 𝑓: 0.033 (940 hom.)
• Consequence: THRB NM_001354712.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.21

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 3-24123019-A-G is Benign according to our data. Variant chr3-24123019-A-G is described in ClinVar as [Benign]. Clinvar id is 257670.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-24123019-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0245 (3734/152298) while in subpopulation NFE AF= 0.0348 (2370/68024). AF 95% confidence interval is 0.0337. There are 80 homozygotes in gnomad4. There are 1927 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 80 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THRB	NM_001354712.2	c.1251T>C	p.Phe417=	synonymous_variant	11/11	ENST00000646209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THRB	ENST00000646209.2	c.1251T>C	p.Phe417=	synonymous_variant	11/11		NM_001354712.2

Frequencies

GnomAD3 genomes AF: 0.0245 AC: 3734 AN: 152180 Hom.: 80 Cov.: 32

Gnomad AFR AF: 0.00637

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0151

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0253

Gnomad FIN AF: 0.0609

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0348

Gnomad OTH AF: 0.0220

GnomAD3 exomes AF: 0.0266 AC: 6683 AN: 251496 Hom.: 128 AF XY: 0.0274 AC XY: 3723 AN XY: 135922

Gnomad AFR exome AF: 0.00504

Gnomad AMR exome AF: 0.0133

Gnomad ASJ exome AF: 0.0109

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0295

Gnomad FIN exome AF: 0.0558

Gnomad NFE exome AF: 0.0328

Gnomad OTH exome AF: 0.0313

GnomAD4 exome AF: 0.0328 AC: 47885 AN: 1461884 Hom.: 940 Cov.: 31 AF XY: 0.0327 AC XY: 23817 AN XY: 727242

Gnomad4 AFR exome AF: 0.00508

Gnomad4 AMR exome AF: 0.0139

Gnomad4 ASJ exome AF: 0.0119

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0310

Gnomad4 FIN exome AF: 0.0548

Gnomad4 NFE exome AF: 0.0353

Gnomad4 OTH exome AF: 0.0290

GnomAD4 genome AF: 0.0245 AC: 3734 AN: 152298 Hom.: 80 Cov.: 32 AF XY: 0.0259 AC XY: 1927 AN XY: 74464

Gnomad4 AFR AF: 0.00635

Gnomad4 AMR AF: 0.0151

Gnomad4 ASJ AF: 0.0121

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.0253

Gnomad4 FIN AF: 0.0609

Gnomad4 NFE AF: 0.0348

Gnomad4 OTH AF: 0.0218

Alfa AF: 0.0273 Hom.: 24

Bravo AF: 0.0199

Asia WGS AF: 0.00779 AC: 27 AN: 3478

EpiCase AF: 0.0323

EpiControl AF: 0.0331

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Sep 06, 2019

- -

Thyroid hormone resistance, generalized, autosomal dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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	-0.45
Cadd	Benign	8.7
Dann	Benign	0.71

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

Publications

LitVar

Other links and lift over

dbSNP: rs13081063; hg19: chr3-24164510;