3-24123019-A-G

Variant names:

• chr3-24123019-A-G
• rs13081063
• NM_001354712.2:c.1251T>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001354712.2(THRB):​c.1251T>C​(p.Phe417Phe) 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:4
• Conservation: PhyloP100: 4.21
• Publications: 4 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 -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 VariationId is 257670.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 80 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001354712.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THRB	NM_001354712.2	MANE Select	c.1251T>C	p.Phe417Phe	synonymous	Exon 11 of 11	NP_001341641.1
	THRB	NM_000461.5		c.1251T>C	p.Phe417Phe	synonymous	Exon 10 of 10	NP_000452.2
	THRB	NM_001128176.3		c.1251T>C	p.Phe417Phe	synonymous	Exon 11 of 11	NP_001121648.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THRB	ENST00000646209.2	MANE Select	c.1251T>C	p.Phe417Phe	synonymous	Exon 11 of 11	ENSP00000496686.2
	THRB	ENST00000356447.9	TSL:1	c.1251T>C	p.Phe417Phe	synonymous	Exon 11 of 11	ENSP00000348827.4
	THRB	ENST00000280696.9	TSL:5	c.1296T>C	p.Phe432Phe	synonymous	Exon 7 of 7	ENSP00000280696.5

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

GnomAD2 exomes AF: 0.0266 AC: 6683 AN: 251496 AF XY: 0.0274

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 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

African (AFR) AF: 0.00508 AC: 170 AN: 33480

American (AMR) AF: 0.0139 AC: 620 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0119 AC: 310 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0310 AC: 2672 AN: 86258

European-Finnish (FIN) AF: 0.0548 AC: 2926 AN: 53420

Middle Eastern (MID) AF: 0.0239 AC: 138 AN: 5768

European-Non Finnish (NFE) AF: 0.0353 AC: 39298 AN: 1112002

Other (OTH) AF: 0.0290 AC: 1749 AN: 60396

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

African (AFR) AF: 0.00635 AC: 264 AN: 41564

American (AMR) AF: 0.0151 AC: 231 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0121 AC: 42 AN: 3472

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5182

South Asian (SAS) AF: 0.0253 AC: 122 AN: 4820

European-Finnish (FIN) AF: 0.0609 AC: 646 AN: 10610

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0348 AC: 2370 AN: 68024

Other (OTH) AF: 0.0218 AC: 46 AN: 2114

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Sep 06, 2019

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	8.7
DANN	Benign	0.71
PhyloP100		4.2
Mutation Taster		=95/5	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: rs13081063; hg19: chr3-24164510;