rs2268458

Positions:

• chr14-80996551-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000369.5(TSHR):​c.170+40701T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.197 in 151,956 control chromosomes in the GnomAD database, including 3,496 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.20 (3496 hom., cov: 32)
• Consequence: TSHR NM_000369.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.291

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.271 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSHR	NM_000369.5	c.170+40701T>C		intron_variant		ENST00000298171.7
TSHR	NM_001018036.3	c.170+40701T>C		intron_variant
TSHR	NM_001142626.3	c.170+40701T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSHR	ENST00000298171.7	c.170+40701T>C		intron_variant		1	NM_000369.5	P1

Frequencies

GnomAD3 genomes AF: 0.197 AC: 29935 AN: 151838 Hom.: 3490 Cov.: 32

Gnomad AFR AF: 0.0764

Gnomad AMI AF: 0.205

Gnomad AMR AF: 0.277

Gnomad ASJ AF: 0.261

Gnomad EAS AF: 0.190

Gnomad SAS AF: 0.180

Gnomad FIN AF: 0.160

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.256

Gnomad OTH AF: 0.213

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.197 AC: 29958 AN: 151956 Hom.: 3496 Cov.: 32 AF XY: 0.192 AC XY: 14292 AN XY: 74256

Gnomad4 AFR AF: 0.0766

Gnomad4 AMR AF: 0.278

Gnomad4 ASJ AF: 0.261

Gnomad4 EAS AF: 0.190

Gnomad4 SAS AF: 0.180

Gnomad4 FIN AF: 0.160

Gnomad4 NFE AF: 0.256

Gnomad4 OTH AF: 0.211

Alfa AF: 0.220 Hom.: 487

Bravo AF: 0.204

Asia WGS AF: 0.215 AC: 749 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.8
DANN	Benign	0.41

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

LitVar

Other links and lift over

dbSNP: rs2268458; hg19: chr14-81462895;