rs1555545033

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS3 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 (★★). ClinVar reports functional evidence for this variant: "SCV002599739: Published functional studies demonstrate a damaging effect (Marelli et al., 2017" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. A263A) has been classified as Likely benign.

• 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
• Publications: 1 publications found

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]

THRA Gene-Disease associations (from GenCC):

• congenital nongoitrous hypothyroidism 6

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002599739: Published functional studies demonstrate a damaging effect (Marelli et al., 2017; Moran et al., 2014)
• 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 hypothyroidism 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 522121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_199334.5. 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
	THRA	NM_199334.5	MANE Select	c.788C>T	p.Ala263Val	missense	Exon 8 of 9	NP_955366.1	Q6FH41
	THRA	NM_001190919.2		c.788C>T	p.Ala263Val	missense	Exon 8 of 10	NP_001177848.1	P10827-1
	THRA	NM_003250.6		c.788C>T	p.Ala263Val	missense	Exon 8 of 10	NP_003241.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THRA	ENST00000450525.7	TSL:1 MANE Select	c.788C>T	p.Ala263Val	missense	Exon 8 of 9	ENSP00000395641.3	P10827-2
	THRA	ENST00000264637.8	TSL:1	c.788C>T	p.Ala263Val	missense	Exon 8 of 10	ENSP00000264637.4	P10827-1
	THRA	ENST00000584985.5	TSL:1	c.788C>T	p.Ala263Val	missense	Exon 8 of 10	ENSP00000463466.1	P10827-3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Congenital nongoitrous hypothyroidism 6 (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Benign	1.4	L
PhyloP100		7.8
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.84	N
REVEL	Pathogenic	0.89
Sift	Benign	0.14	T
Sift4G	Benign	0.76	T
Polyphen		0.98	D
Vest4		0.88
MutPred		0.75		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
Mutation Taster		=2/98	disease causing (ClinVar)

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