14-80955814-A-G

Position:

• chr14-80955814-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000369.5(TSHR):​c.134A>G​(p.Gln45Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSHR NM_000369.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.20

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]

CEP128 (HGNC:20359): (centrosomal protein 128) Involved in protein localization. Located in centriole and spindle pole. Part of centriolar subdistal appendage. [provided by Alliance of Genome Resources, Apr 2022]

TSHR (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10221037).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSHR	NM_000369.5	c.134A>G	p.Gln45Arg	missense_variant	1/10	ENST00000298171.7	NP_000360.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSHR	ENST00000298171.7	c.134A>G	p.Gln45Arg	missense_variant	1/10	1	NM_000369.5	ENSP00000298171.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000611 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 13, 2023

The c.134A>G (p.Q45R) alteration is located in exon 1 (coding exon 1) of the TSHR gene. This alteration results from a A to G substitution at nucleotide position 134, causing the glutamine (Q) at amino acid position 45 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	19
DANN	Benign	0.94
DEOGEN2	Benign	0.23	.;.;.;.;T;.
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.59	.;T;T;T;T;T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.10	T;T;T;T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.0	.;N;.;.;.;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.48	N;N;N;.;N;N
REVEL	Benign	0.17
Sift	Benign	0.54	T;T;T;.;T;T
Sift4G	Benign	0.53	T;T;T;.;T;T
Polyphen		0.0040	.;B;.;.;.;.
Vest4		0.17
MutPred		0.27		Gain of catalytic residue at L50 (P = 0.0549);Gain of catalytic residue at L50 (P = 0.0549);Gain of catalytic residue at L50 (P = 0.0549);Gain of catalytic residue at L50 (P = 0.0549);Gain of catalytic residue at L50 (P = 0.0549);Gain of catalytic residue at L50 (P = 0.0549);
MVP		0.93
MPC		0.17
ClinPred		0.28	T
GERP RS		5.2
gMVP		0.46

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-81422158;