rs121908879

Positions:

• chr14-81096641-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_000369.5(TSHR):​c.548A>G​(p.Lys183Arg) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSHR NM_000369.5 missense, splice_region
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.38

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-81096641-A-G is Pathogenic according to our data. Variant chr14-81096641-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 6453.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.28534395). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSHR	NM_000369.5	c.548A>G	p.Lys183Arg	missense_variant, splice_region_variant	7/10	ENST00000298171.7
LOC101928462	XR_001751022.2	n.616-2317T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSHR	ENST00000298171.7	c.548A>G	p.Lys183Arg	missense_variant, splice_region_variant	7/10	1	NM_000369.5	P1
	ENST00000646052.2	n.639-2317T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Familial gestational hyperthyroidism Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 17, 1998

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	.;.;.;D;.
Eigen	Benign	-0.23
Eigen_PC	Benign	0.033
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.89	.;D;D;D;D
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.29	T;T;T;T;T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	0.70	.;N;.;.;N
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.060	N;N;N;N;N
REVEL	Uncertain	0.43
Sift	Benign	0.70	T;T;T;T;T
Sift4G	Benign	0.87	T;T;T;T;T
Polyphen		0.12	.;B;.;.;.
Vest4		0.82
MutPred		0.71		Gain of catalytic residue at T181 (P = 0.0084);Gain of catalytic residue at T181 (P = 0.0084);Gain of catalytic residue at T181 (P = 0.0084);Gain of catalytic residue at T181 (P = 0.0084);Gain of catalytic residue at T181 (P = 0.0084);
MVP		0.98
MPC		0.19
ClinPred		0.94	D
GERP RS		6.0
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs121908879; hg19: chr14-81562985;