3-24143591-G-C

Variant names:

• chr3-24143591-G-C
• rs143993214
• NM_001354712.2:c.648C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001354712.2(THRB):​c.648C>G​(p.Asp216Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,614,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D216D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: THRB NM_001354712.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.132
• 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: SD, AD Classification: STRONG Submitted by: PanelApp Australia, 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)

THRB-AS2 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the THRB gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 58 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: 2.5652 (below the threshold of 3.09). Trascript score misZ: 3.708 (above the threshold of 3.09). GenCC associations: The gene is linked to thyroid hormone resistance, generalized, autosomal dominant, resistance to thyroid hormone due to a mutation in thyroid hormone receptor beta, thyroid hormone resistance, generalized, autosomal recessive.
• BP4: Computational evidence support a benign effect (MetaRNN=0.06950086).

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.648C>G	p.Asp216Glu	missense	Exon 8 of 11	NP_001341641.1	P10828-1
	THRB	NM_000461.5		c.648C>G	p.Asp216Glu	missense	Exon 7 of 10	NP_000452.2
	THRB	NM_001128176.3		c.648C>G	p.Asp216Glu	missense	Exon 8 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.648C>G	p.Asp216Glu	missense	Exon 8 of 11	ENSP00000496686.2	P10828-1
	THRB	ENST00000356447.9	TSL:1	c.648C>G	p.Asp216Glu	missense	Exon 8 of 11	ENSP00000348827.4	P10828-1
	THRB	ENST00000280696.9	TSL:5	c.693C>G	p.Asp231Glu	missense	Exon 4 of 7	ENSP00000280696.5	P10828-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461886 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152258 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74448

African (AFR) AF: 0.00 AC: 0 AN: 41558

American (AMR) AF: 0.00 AC: 0 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2112

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	5.5
DANN	Benign	0.80
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.070	T
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.13
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.050	N
REVEL	Benign	0.27
Sift	Benign	0.60	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.26
MutPred		0.30		Gain of glycosylation at T215 (P = 0.0126)
MVP		0.28
MPC		1.1
ClinPred		0.025	T
GERP RS		-1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.60
Mutation Taster		=78/22	polymorphism

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: rs143993214; hg19: chr3-24185082;