14-81092563-T-A

Position:

• chr14-81092563-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The ENST00000298171.7(TSHR):​c.500T>A​(p.Ile167Asn) variant causes a missense change. 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSHR ENST00000298171.7 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.70

Genes affected

TSHR (HGNC:12373): (thyroid stimulating hormone receptor) The protein encoded by this gene is a membrane protein and a major controller of thyroid cell metabolism. The encoded protein is a receptor for thyrothropin and thyrostimulin, and its activity is mediated by adenylate cyclase. Defects in this gene are a cause of several types of hyperthyroidism. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

(HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in ENST00000298171.7
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.955
• PP5: Variant 14-81092563-T-A is Pathogenic according to our data. Variant chr14-81092563-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 6434.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSHR	NM_000369.5	c.500T>A	p.Ile167Asn	missense_variant	6/10	ENST00000298171.7	NP_000360.2
LOC101928462	XR_001751022.2	n.881+1019A>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSHR	ENST00000298171.7	c.500T>A	p.Ile167Asn	missense_variant	6/10	1	NM_000369.5	ENSP00000298171	P1
	ENST00000646052.2	n.904+1019A>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hypothyroidism due to TSH receptor mutations Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 19, 1995

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	.;.;.;D;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.92	.;D;D;D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	.;M;.;.;M
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-5.4	D;D;D;D;D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	.;D;.;.;.
Vest4		0.90
MutPred		0.80		Gain of catalytic residue at F172 (P = 0.0016);Gain of catalytic residue at F172 (P = 0.0016);Gain of catalytic residue at F172 (P = 0.0016);Gain of catalytic residue at F172 (P = 0.0016);Gain of catalytic residue at F172 (P = 0.0016);
MVP		1.0
MPC		0.87
ClinPred		1.0	D
GERP RS		5.3
gMVP		0.97

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: rs121908862; hg19: chr14-81558907;