chr14-81109110-T-C

Variant names:

• chr14-81109110-T-C
• rs8017455
• NM_000369.5:c.692+658T>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.692+658T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.207 in 152,080 control chromosomes in the GnomAD database, including 3,585 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 0.21 (3585 hom., cov: 31)
• Consequence: TSHR NM_000369.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.339
• Publications: 10 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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.316 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.692+658T>C		intron	N/A	NP_000360.2
	TSHR	NM_001142626.3		c.*429T>C		downstream_gene	N/A	NP_001136098.1
	TSHR	NM_001018036.3		c.*429T>C		downstream_gene	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.692+658T>C		intron	N/A	ENSP00000298171.2
	TSHR	ENST00000541158.6	TSL:5	c.692+658T>C		intron	N/A	ENSP00000441235.2
	TSHR	ENST00000636454.1	TSL:5	n.610+658T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.207 AC: 31406 AN: 151962 Hom.: 3584 Cov.: 31

Gnomad AFR AF: 0.292

Gnomad AMI AF: 0.289

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.329

Gnomad SAS AF: 0.123

Gnomad FIN AF: 0.204

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.172

Gnomad OTH AF: 0.166

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

GnomAD4 genome AF: 0.207 AC: 31435 AN: 152080 Hom.: 3585 Cov.: 31 AF XY: 0.207 AC XY: 15368 AN XY: 74328

African (AFR) AF: 0.292 AC: 12120 AN: 41450

American (AMR) AF: 0.137 AC: 2094 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 430 AN: 3472

East Asian (EAS) AF: 0.329 AC: 1701 AN: 5164

South Asian (SAS) AF: 0.122 AC: 589 AN: 4818

European-Finnish (FIN) AF: 0.204 AC: 2162 AN: 10588

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.172 AC: 11697 AN: 67986

Other (OTH) AF: 0.164 AC: 346 AN: 2108

Alfa AF: 0.179 Hom.: 8586

Bravo AF: 0.208

Asia WGS AF: 0.173 AC: 600 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.3
DANN	Benign	0.41
PhyloP100		0.34
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: rs8017455; hg19: chr14-81575454;