rs17111530

Variant names:

• chr14-81132568-T-C
• rs17111530
• NM_000369.5:c.693-7111T>C

Variant summary

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

The NM_000369.5(TSHR):​c.693-7111T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.156 in 152,152 control chromosomes in the GnomAD database, including 3,448 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 0.16 (3448 hom., cov: 32)
• Consequence: TSHR NM_000369.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.20
• Publications: 8 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

ENSG00000284959 (HGNC:58172):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.375 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSHR	NM_000369.5	c.693-7111T>C		intron_variant	Intron 8 of 9	ENST00000298171.7	NP_000360.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSHR	ENST00000298171.7	c.693-7111T>C		intron_variant	Intron 8 of 9	1	NM_000369.5	ENSP00000298171.2

Frequencies

GnomAD3 genomes AF: 0.156 AC: 23691 AN: 152034 Hom.: 3444 Cov.: 32

Gnomad AFR AF: 0.380

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0818

Gnomad ASJ AF: 0.0822

Gnomad EAS AF: 0.237

Gnomad SAS AF: 0.169

Gnomad FIN AF: 0.0493

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.0517

Gnomad OTH AF: 0.144

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

GnomAD4 genome AF: 0.156 AC: 23721 AN: 152152 Hom.: 3448 Cov.: 32 AF XY: 0.155 AC XY: 11520 AN XY: 74396

African (AFR) AF: 0.380 AC: 15763 AN: 41436

American (AMR) AF: 0.0815 AC: 1246 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0822 AC: 285 AN: 3468

East Asian (EAS) AF: 0.236 AC: 1225 AN: 5182

South Asian (SAS) AF: 0.169 AC: 815 AN: 4828

European-Finnish (FIN) AF: 0.0493 AC: 523 AN: 10612

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.0516 AC: 3512 AN: 68016

Other (OTH) AF: 0.142 AC: 299 AN: 2110

Alfa AF: 0.0831 Hom.: 2050

Bravo AF: 0.167

Asia WGS AF: 0.205 AC: 711 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	11
DANN	Benign	0.55
PhyloP100		1.2
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: rs17111530; hg19: chr14-81598912;