rs13081063

Positions:

chr3-24123019-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 4.21

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 GnomAd4 at 80 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
THRB	NM_001354712.2 linkuse as main transcript	c.1251T>C	p.Phe417=	synonymous_variant	11/11	ENST00000646209.2	NP_001341641.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
THRB	ENST00000646209.2 linkuse as main transcript	c.1251T>C	p.Phe417=	synonymous_variant	11/11		NM_001354712.2	ENSP00000496686		P10828-1

Frequencies

GnomAD3 genomes

AF:

0.0245

AC:

3734

AN:

152180

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0327

AC XY:

23817

AN XY:

727242

show subpopulations

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.:

Cov.:

AF XY:

0.0259

AC XY:

1927

AN XY:

74464

show subpopulations

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.:

Bravo

AF:

0.0199

Asia WGS

AF:

0.00779

AC:

AN:

3478

EpiCase

AF:

0.0323

EpiControl

AF:

0.0331

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 06, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over