rs121908867

Positions:

• chr14-81143028-C-A
• chr14-81143028-C-T

Variant summary

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

The NM_000369.5(TSHR):​c.970C>A​(p.Gln324Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q324Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TSHR NM_000369.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.04

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1580832).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSHR	NM_000369.5	c.970C>A	p.Gln324Lys	missense_variant	10/10	ENST00000298171.7
LOC101928462	XR_001751022.2	n.487+22165G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSHR	ENST00000298171.7	c.970C>A	p.Gln324Lys	missense_variant	10/10	1	NM_000369.5	P1
	ENST00000646052.2	n.510+22165G>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	19
DANN	Benign	0.96
Eigen	Benign	-0.11
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.64	.;T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-0.84	T
MutationTaster	Benign	0.99	D;D
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.64	N;N
REVEL	Benign	0.17
Sift	Benign	0.22	T;T
Sift4G	Benign	1.0	T;T
Vest4		0.089
MutPred		0.42		Gain of catalytic residue at L322 (P = 0.0055);Gain of catalytic residue at L322 (P = 0.0055);
MVP		0.95
MPC		0.21
ClinPred		0.40	T
GERP RS		5.8
gMVP		0.68

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: chr14-81609372;