14-80964501-A-G

Variant names:

• chr14-80964501-A-G
• rs2284716
• NM_000369.5:c.170+8651A>G

Variant summary

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

The NM_000369.5(TSHR):​c.170+8651A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.178 in 152,142 control chromosomes in the GnomAD database, including 2,726 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 0.18 (2726 hom., cov: 32)
• Consequence: TSHR NM_000369.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.511
• Publications: 6 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.417 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000369.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSHR	NM_000369.5	MANE Select	c.170+8651A>G		intron	N/A	NP_000360.2
	TSHR	NM_001142626.3		c.170+8651A>G		intron	N/A	NP_001136098.1
	TSHR	NM_001018036.3		c.170+8651A>G		intron	N/A	NP_001018046.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSHR	ENST00000298171.7	TSL:1 MANE Select	c.170+8651A>G		intron	N/A	ENSP00000298171.2
	TSHR	ENST00000554435.1	TSL:1	c.170+8651A>G		intron	N/A	ENSP00000450549.1
	TSHR	ENST00000342443.10	TSL:1	c.170+8651A>G		intron	N/A	ENSP00000340113.6

Frequencies

GnomAD3 genomes AF: 0.178 AC: 27102 AN: 152024 Hom.: 2719 Cov.: 32

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.157

Gnomad AMR AF: 0.204

Gnomad ASJ AF: 0.177

Gnomad EAS AF: 0.432

Gnomad SAS AF: 0.149

Gnomad FIN AF: 0.264

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.165

Gnomad OTH AF: 0.179

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

GnomAD4 genome AF: 0.178 AC: 27128 AN: 152142 Hom.: 2726 Cov.: 32 AF XY: 0.184 AC XY: 13656 AN XY: 74372

African (AFR) AF: 0.141 AC: 5868 AN: 41500

American (AMR) AF: 0.205 AC: 3127 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.177 AC: 614 AN: 3466

East Asian (EAS) AF: 0.432 AC: 2237 AN: 5182

South Asian (SAS) AF: 0.149 AC: 719 AN: 4830

European-Finnish (FIN) AF: 0.264 AC: 2790 AN: 10576

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.165 AC: 11204 AN: 67992

Other (OTH) AF: 0.184 AC: 390 AN: 2114

Alfa AF: 0.164 Hom.: 424

Bravo AF: 0.175

Asia WGS AF: 0.265 AC: 918 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.8
DANN	Benign	0.70
PhyloP100		0.51
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: rs2284716; hg19: chr14-81430845;