NM_199334.5:c.788C>T

Variant names:

• chr17-40088306-C-T
• rs1555545033
• NM_199334.5:c.788C>T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_199334.5(THRA):​c.788C>T​(p.Ala263Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: THRA NM_199334.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.82

Genes affected

THRA (HGNC:11796): (thyroid hormone receptor alpha) 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. Alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the THRA gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 3.4693 (above the threshold of 3.09). Trascript score misZ: 4.6029 (above the threshold of 3.09). GenCC associations: The gene is linked to congenital nongoitrous hypothryoidism 6.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.929
• PP5: Variant 17-40088306-C-T is Pathogenic according to our data. Variant chr17-40088306-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 522121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THRA	NM_199334.5	c.788C>T	p.Ala263Val	missense_variant	Exon 8 of 9	ENST00000450525.7	NP_955366.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THRA	ENST00000450525.7	c.788C>T	p.Ala263Val	missense_variant	Exon 8 of 9	1	NM_199334.5	ENSP00000395641.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Oct 04, 2017

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Nov 05, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect (Marelli et al., 2017; Moran et al., 2014); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32349464, 27144938, 27809680, 28471274, 24969835, 26037512, 27381958, 30842990, 33509032) -

Congenital nongoitrous hypothyroidism 6 Pathogenic:1

Jan 12, 2022

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.61	D;.;D;.;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.99	.;D;D;.;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Benign	1.4	L;L;L;L;L
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.84	N;.;N;N;N
REVEL	Pathogenic	0.89
Sift	Benign	0.14	T;.;T;T;T
Sift4G	Benign	0.76	T;T;T;T;T
Polyphen		0.98	D;D;D;.;.
Vest4		0.88
MutPred		0.75		Loss of disorder (P = 0.1289);Loss of disorder (P = 0.1289);Loss of disorder (P = 0.1289);Loss of disorder (P = 0.1289);Loss of disorder (P = 0.1289);
MVP		0.99
MPC		1.6
ClinPred		0.90	D
GERP RS		5.0
Varity_R		0.47
gMVP		0.96

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: rs1555545033; hg19: chr17-38244559; COSMIC: COSV99225882; COSMIC: COSV99225882;