rs2268451

Positions:

• chr14-80957774-T-G

Variant summary

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

The NM_000369.5(TSHR):​c.170+1924T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.499 in 152,098 control chromosomes in the GnomAD database, including 20,489 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 0.50 (20487 hom., cov: 32)
  • Exomes 𝑓: 0.38 (2 hom.)
• Consequence: TSHR NM_000369.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.43

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.7 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSHR	NM_000369.5	c.170+1924T>G		intron_variant		ENST00000298171.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSHR	ENST00000298171.7	c.170+1924T>G		intron_variant		1	NM_000369.5	P1

Frequencies

GnomAD3 genomes AF: 0.499 AC: 75788 AN: 151956 Hom.: 20457 Cov.: 32

Gnomad AFR AF: 0.707

Gnomad AMI AF: 0.557

Gnomad AMR AF: 0.447

Gnomad ASJ AF: 0.545

Gnomad EAS AF: 0.223

Gnomad SAS AF: 0.501

Gnomad FIN AF: 0.309

Gnomad MID AF: 0.558

Gnomad NFE AF: 0.431

Gnomad OTH AF: 0.495

GnomAD4 exome AF: 0.375 AC: 9 AN: 24 Hom.: 2 Cov.: 0 AF XY: 0.409 AC XY: 9 AN XY: 22

Gnomad4 ASJ exome AF: 0.500

Gnomad4 FIN exome AF: 0.500

Gnomad4 NFE exome AF: 0.167

Gnomad4 OTH exome AF: 0.667

GnomAD4 genome AF: 0.499 AC: 75864 AN: 152074 Hom.: 20487 Cov.: 32 AF XY: 0.490 AC XY: 36412 AN XY: 74344

Gnomad4 AFR AF: 0.707

Gnomad4 AMR AF: 0.447

Gnomad4 ASJ AF: 0.545

Gnomad4 EAS AF: 0.223

Gnomad4 SAS AF: 0.501

Gnomad4 FIN AF: 0.309

Gnomad4 NFE AF: 0.431

Gnomad4 OTH AF: 0.491

Alfa AF: 0.474 Hom.: 2773

Bravo AF: 0.521

Asia WGS AF: 0.407 AC: 1418 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	7.2
DANN	Benign	0.60

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: rs2268451; hg19: chr14-81424118;