rs121908879

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP5BP4

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

Scores

2
5
12

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 5.38
Variant links:
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]

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ACMG classification

Classification made for transcript

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
TSHRNM_000369.5 linkuse as main transcriptc.548A>G p.Lys183Arg missense_variant, splice_region_variant 7/10 ENST00000298171.7
LOC101928462XR_001751022.2 linkuse as main transcriptn.616-2317T>C intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TSHRENST00000298171.7 linkuse as main transcriptc.548A>G p.Lys183Arg missense_variant, splice_region_variant 7/101 NM_000369.5 P1
ENST00000646052.2 linkuse as main transcriptn.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
LINK: link

Submissions by phenotype

Familial gestational hyperthyroidism Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMDec 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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121908879; hg19: chr14-81562985; API