rs121908869

chr14-80955802-G-Achr14-80955802-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The NM_000369.5(TSHR):c.122G>A(p.Cys41Tyr) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C41S) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSHR NM_000369.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.58

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-80955802-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 6442.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.76

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSHR	NM_000369.5	c.122G>A	p.Cys41Tyr	missense_variant	1/10	ENST00000298171.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSHR	ENST00000298171.7	c.122G>A	p.Cys41Tyr	missense_variant	1/10	1	NM_000369.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
Cadd	Pathogenic	30
Dann	Uncertain	1.0
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.77	D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.76	D;D;D;D;D;D
MetaSVM	Uncertain	0.40	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.7	D;D;D;.;D;D
REVEL	Uncertain	0.59
Sift	Uncertain	0.013	D;D;D;.;D;D
Sift4G	Uncertain	0.0020	D;D;D;.;D;D
Polyphen		1.0	.;D;.;.;.;.
Vest4		0.85
MutPred		0.46		Loss of methylation at K42 (P = 0.0165);Loss of methylation at K42 (P = 0.0165);Loss of methylation at K42 (P = 0.0165);Loss of methylation at K42 (P = 0.0165);Loss of methylation at K42 (P = 0.0165);Loss of methylation at K42 (P = 0.0165);
MVP		0.99
MPC		0.87
ClinPred		0.98	D
GERP RS		5.2
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr14-81422146;