chr14-80955814-A-G

Variant names:

• chr14-80955814-A-G
• NM_000369.5:c.134A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 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. 16/21 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
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 43 curated pathogenic missense variants (we use a threshold of 10). The gene has 11 curated benign missense variants. Gene score misZ: 0.33445 (below the threshold of 3.09). Trascript score misZ: 1.3127 (below the threshold of 3.09). GenCC associations: The gene is linked to athyreosis, hypothyroidism due to TSH receptor mutations, familial hyperthyroidism due to mutations in TSH receptor, familial gestational hyperthyroidism, thyroid hypoplasia.
• BP4: Computational evidence support a benign effect (MetaRNN=0.10221037).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000369.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSHR	NM_000369.5	MANE Select	c.134A>G	p.Gln45Arg	missense	Exon 1 of 10	NP_000360.2	P16473-1
	TSHR	NM_001142626.3		c.134A>G	p.Gln45Arg	missense	Exon 1 of 9	NP_001136098.1	P16473-3
	TSHR	NM_001018036.3		c.134A>G	p.Gln45Arg	missense	Exon 1 of 9	NP_001018046.1	P16473-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSHR	ENST00000298171.7	TSL:1 MANE Select	c.134A>G	p.Gln45Arg	missense	Exon 1 of 10	ENSP00000298171.2	P16473-1
	TSHR	ENST00000554435.1	TSL:1	c.134A>G	p.Gln45Arg	missense	Exon 1 of 9	ENSP00000450549.1	P16473-3
	TSHR	ENST00000342443.10	TSL:1	c.134A>G	p.Gln45Arg	missense	Exon 1 of 9	ENSP00000340113.6	P16473-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000611 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.0	N
PhyloP100		5.2
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.17
Sift	Benign	0.54	T
Sift4G	Benign	0.53	T
Polyphen		0.0040	B
Vest4		0.17
MutPred		0.27		Gain of catalytic residue at L50 (P = 0.0549)
MVP		0.93
MPC		0.17
ClinPred		0.28	T
GERP RS		5.2
PromoterAI		0.053	Neutral
gMVP		0.46
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

hg19: chr14-81422158;