chr14-81128036-C-T

Variant names:

• chr14-81128036-C-T
• rs3783938
• NM_000369.5:c.693-11643C>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.693-11643C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.129 in 152,064 control chromosomes in the GnomAD database, including 1,733 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 0.13 (1733 hom., cov: 32)
• Consequence: TSHR NM_000369.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.456
• Publications: 16 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=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.261 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSHR	NM_000369.5	c.693-11643C>T		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.693-11643C>T		intron_variant	Intron 8 of 9	1	NM_000369.5	ENSP00000298171.2

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19652 AN: 151944 Hom.: 1736 Cov.: 32

Gnomad AFR AF: 0.219

Gnomad AMI AF: 0.157

Gnomad AMR AF: 0.0539

Gnomad ASJ AF: 0.122

Gnomad EAS AF: 0.234

Gnomad SAS AF: 0.274

Gnomad FIN AF: 0.146

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0715

Gnomad OTH AF: 0.110

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

GnomAD4 genome AF: 0.129 AC: 19653 AN: 152064 Hom.: 1733 Cov.: 32 AF XY: 0.135 AC XY: 10020 AN XY: 74320

African (AFR) AF: 0.219 AC: 9087 AN: 41452

American (AMR) AF: 0.0537 AC: 822 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.122 AC: 424 AN: 3470

East Asian (EAS) AF: 0.233 AC: 1208 AN: 5178

South Asian (SAS) AF: 0.273 AC: 1313 AN: 4810

European-Finnish (FIN) AF: 0.146 AC: 1537 AN: 10546

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0715 AC: 4863 AN: 67996

Other (OTH) AF: 0.109 AC: 229 AN: 2110

Alfa AF: 0.0937 Hom.: 2141

Bravo AF: 0.124

Asia WGS AF: 0.232 AC: 805 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	2.4
DANN	Benign	0.67
PhyloP100		-0.46
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: rs3783938; hg19: chr14-81594380;