NM_000369.5:c.170+40701T>C

Variant names:

• chr14-80996551-T-C
• rs2268458
• NM_000369.5:c.170+40701T>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.170+40701T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.197 in 151,956 control chromosomes in the GnomAD database, including 3,496 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 0.20 (3496 hom., cov: 32)
• Consequence: TSHR NM_000369.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.291
• Publications: 24 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=-0.86).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.271 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+40701T>C		intron	N/A	NP_000360.2
	TSHR	NM_001142626.3		c.170+40701T>C		intron	N/A	NP_001136098.1
	TSHR	NM_001018036.3		c.170+40701T>C		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+40701T>C		intron	N/A	ENSP00000298171.2
	TSHR	ENST00000554435.1	TSL:1	c.170+40701T>C		intron	N/A	ENSP00000450549.1
	TSHR	ENST00000342443.10	TSL:1	c.170+40701T>C		intron	N/A	ENSP00000340113.6

Frequencies

GnomAD3 genomes AF: 0.197 AC: 29935 AN: 151838 Hom.: 3490 Cov.: 32

Gnomad AFR AF: 0.0764

Gnomad AMI AF: 0.205

Gnomad AMR AF: 0.277

Gnomad ASJ AF: 0.261

Gnomad EAS AF: 0.190

Gnomad SAS AF: 0.180

Gnomad FIN AF: 0.160

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.256

Gnomad OTH AF: 0.213

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

GnomAD4 genome AF: 0.197 AC: 29958 AN: 151956 Hom.: 3496 Cov.: 32 AF XY: 0.192 AC XY: 14292 AN XY: 74256

African (AFR) AF: 0.0766 AC: 3174 AN: 41458

American (AMR) AF: 0.278 AC: 4230 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.261 AC: 906 AN: 3468

East Asian (EAS) AF: 0.190 AC: 976 AN: 5138

South Asian (SAS) AF: 0.180 AC: 867 AN: 4818

European-Finnish (FIN) AF: 0.160 AC: 1686 AN: 10538

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.256 AC: 17434 AN: 67986

Other (OTH) AF: 0.211 AC: 446 AN: 2114

Alfa AF: 0.220 Hom.: 487

Bravo AF: 0.204

Asia WGS AF: 0.215 AC: 749 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.8
DANN	Benign	0.41
PhyloP100		0.29
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: rs2268458; hg19: chr14-81462895;