rs2284735

Variant names:

• chr14-81087442-A-G
• rs2284735
• NM_000369.5:c.318-512A>G

Your query was ambiguous. Multiple possible variants found:

• chr14-81087442-A-G
• chr14-81087442-A-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000369.5(TSHR):​c.318-512A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.476 in 180,886 control chromosomes in the GnomAD database, including 24,523 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 0.46 (19585 hom., cov: 32)
  • Exomes 𝑓: 0.57 (4938 hom.)
• Consequence: TSHR NM_000369.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.119
• Publications: 7 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]

TSHR Gene-Disease associations (from GenCC):

• familial gestational hyperthyroidism

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• hypothyroidism due to TSH receptor mutations

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• familial hyperthyroidism due to mutations in TSH receptor

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• athyreosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• thyroid hypoplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

TSHR-AS1 (HGNC:58172):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.612 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSHR	NM_000369.5	c.318-512A>G		intron_variant	Intron 3 of 9	ENST00000298171.7	NP_000360.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSHR	ENST00000298171.7	c.318-512A>G		intron_variant	Intron 3 of 9	1	NM_000369.5	ENSP00000298171.2

Frequencies

GnomAD3 genomes AF: 0.458 AC: 69619 AN: 151858 Hom.: 19589 Cov.: 32

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.391

Gnomad AMR AF: 0.524

Gnomad ASJ AF: 0.586

Gnomad EAS AF: 0.423

Gnomad SAS AF: 0.456

Gnomad FIN AF: 0.642

Gnomad MID AF: 0.541

Gnomad NFE AF: 0.617

Gnomad OTH AF: 0.500

GnomAD4 exome AF: 0.568 AC: 16412 AN: 28910 Hom.: 4938 Cov.: 0 AF XY: 0.553 AC XY: 8312 AN XY: 15022

African (AFR) AF: 0.118 AC: 36 AN: 304

American (AMR) AF: 0.593 AC: 1867 AN: 3150

Ashkenazi Jewish (ASJ) AF: 0.527 AC: 238 AN: 452

East Asian (EAS) AF: 0.405 AC: 694 AN: 1714

South Asian (SAS) AF: 0.442 AC: 1548 AN: 3504

European-Finnish (FIN) AF: 0.661 AC: 600 AN: 908

Middle Eastern (MID) AF: 0.500 AC: 40 AN: 80

European-Non Finnish (NFE) AF: 0.609 AC: 10557 AN: 17334

Other (OTH) AF: 0.568 AC: 832 AN: 1464

GnomAD4 genome AF: 0.458 AC: 69625 AN: 151976 Hom.: 19585 Cov.: 32 AF XY: 0.456 AC XY: 33863 AN XY: 74262

African (AFR) AF: 0.120 AC: 4971 AN: 41470

American (AMR) AF: 0.524 AC: 8004 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.586 AC: 2032 AN: 3468

East Asian (EAS) AF: 0.423 AC: 2176 AN: 5150

South Asian (SAS) AF: 0.458 AC: 2199 AN: 4806

European-Finnish (FIN) AF: 0.642 AC: 6766 AN: 10540

Middle Eastern (MID) AF: 0.534 AC: 157 AN: 294

European-Non Finnish (NFE) AF: 0.617 AC: 41909 AN: 67954

Other (OTH) AF: 0.500 AC: 1056 AN: 2114

Alfa AF: 0.576 Hom.: 62342

Bravo AF: 0.437

Asia WGS AF: 0.403 AC: 1399 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	2.4
DANN	Benign	0.61
PhyloP100		-0.12
Mutation Taster		=100/0	polymorphism (auto)

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

dbSNP: rs2284735; hg19: chr14-81553786; COSMIC: COSV107314910;