NM_001354712.2:c.*5352C>T

Variant names:

• chr3-24117532-G-A
• rs56204436
• NM_001354712.2:c.*5352C>T

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.*5352C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.114 in 152,266 control chromosomes in the GnomAD database, including 1,502 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1502 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: THRB NM_001354712.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0300
• Publications: 2 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=-0.87).
• BP6: Variant 3-24117532-G-A is Benign according to our data. Variant chr3-24117532-G-A is described in ClinVar as Benign. ClinVar VariationId is 344538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.234 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THRB	NM_001354712.2	MANE Select	c.*5352C>T		3_prime_UTR	Exon 11 of 11	NP_001341641.1	P10828-1
	THRB	NM_000461.5		c.*5352C>T		3_prime_UTR	Exon 10 of 10	NP_000452.2
	THRB	NM_001128176.3		c.*5352C>T		3_prime_UTR	Exon 11 of 11	NP_001121648.1	P10828-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THRB	ENST00000646209.2	MANE Select	c.*5352C>T		3_prime_UTR	Exon 11 of 11	ENSP00000496686.2	P10828-1
	THRB	ENST00000396671.7	TSL:5	c.*5352C>T		3_prime_UTR	Exon 10 of 10	ENSP00000379904.2	P10828-1

Frequencies

GnomAD3 genomes AF: 0.114 AC: 17324 AN: 152148 Hom.: 1502 Cov.: 33

Gnomad AFR AF: 0.238

Gnomad AMI AF: 0.0899

Gnomad AMR AF: 0.0692

Gnomad ASJ AF: 0.0640

Gnomad EAS AF: 0.0535

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.0896

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0604

Gnomad OTH AF: 0.108

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 6 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 4

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) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 6

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.114 AC: 17337 AN: 152266 Hom.: 1502 Cov.: 33 AF XY: 0.114 AC XY: 8454 AN XY: 74450

African (AFR) AF: 0.238 AC: 9890 AN: 41518

American (AMR) AF: 0.0690 AC: 1056 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0640 AC: 222 AN: 3468

East Asian (EAS) AF: 0.0538 AC: 279 AN: 5184

South Asian (SAS) AF: 0.102 AC: 492 AN: 4822

European-Finnish (FIN) AF: 0.0896 AC: 951 AN: 10616

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0604 AC: 4112 AN: 68036

Other (OTH) AF: 0.107 AC: 227 AN: 2116

Alfa AF: 0.0835 Hom.: 1186

Bravo AF: 0.114

Asia WGS AF: 0.117 AC: 407 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Thyroid hormone resistance, generalized, autosomal dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.1
DANN	Benign	0.69
PhyloP100		0.030
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: rs56204436; hg19: chr3-24159023;