rs7144481

Variant names:

• chr14-81144598-C-T
• rs7144481
• NM_000369.5:c.*245C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000369.5(TSHR):​c.*245C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.855 in 564,592 control chromosomes in the GnomAD database, including 206,631 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.85 (55136 hom., cov: 31)
  • Exomes 𝑓: 0.86 (151495 hom.)
• Consequence: TSHR NM_000369.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.360
• Publications: 18 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

TSHR-AS1 (HGNC:58172):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BP6: Variant 14-81144598-C-T is Benign according to our data. Variant chr14-81144598-C-T is described in ClinVar as Benign. ClinVar VariationId is 314705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.859 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSHR	NM_000369.5	MANE Select	c.*245C>T		3_prime_UTR	Exon 10 of 10	NP_000360.2	P16473-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSHR	ENST00000298171.7	TSL:1 MANE Select	c.*245C>T		3_prime_UTR	Exon 10 of 10	ENSP00000298171.2	P16473-1
	TSHR	ENST00000541158.6	TSL:5	c.*245C>T		3_prime_UTR	Exon 11 of 11	ENSP00000441235.2	P16473-1
	TSHR	ENST00000637447.1	TSL:5	n.*245C>T		non_coding_transcript_exon	Exon 1 of 2	ENSP00000490136.1	A0A1B0GUJ5

Frequencies

GnomAD3 genomes AF: 0.851 AC: 129387 AN: 152054 Hom.: 55091 Cov.: 31

Gnomad AFR AF: 0.856

Gnomad AMI AF: 0.849

Gnomad AMR AF: 0.817

Gnomad ASJ AF: 0.825

Gnomad EAS AF: 0.837

Gnomad SAS AF: 0.866

Gnomad FIN AF: 0.800

Gnomad MID AF: 0.801

Gnomad NFE AF: 0.865

Gnomad OTH AF: 0.844

GnomAD4 exome AF: 0.856 AC: 353174 AN: 412418 Hom.: 151495 Cov.: 3 AF XY: 0.857 AC XY: 187323 AN XY: 218600

African (AFR) AF: 0.855 AC: 10126 AN: 11844

American (AMR) AF: 0.835 AC: 14381 AN: 17228

Ashkenazi Jewish (ASJ) AF: 0.830 AC: 10554 AN: 12712

East Asian (EAS) AF: 0.850 AC: 23989 AN: 28218

South Asian (SAS) AF: 0.860 AC: 37790 AN: 43942

European-Finnish (FIN) AF: 0.811 AC: 19931 AN: 24570

Middle Eastern (MID) AF: 0.794 AC: 1411 AN: 1776

European-Non Finnish (NFE) AF: 0.864 AC: 214604 AN: 248260

Other (OTH) AF: 0.854 AC: 20388 AN: 23868

GnomAD4 genome AF: 0.851 AC: 129488 AN: 152174 Hom.: 55136 Cov.: 31 AF XY: 0.847 AC XY: 62995 AN XY: 74376

African (AFR) AF: 0.856 AC: 35553 AN: 41520

American (AMR) AF: 0.816 AC: 12479 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.825 AC: 2862 AN: 3470

East Asian (EAS) AF: 0.837 AC: 4329 AN: 5172

South Asian (SAS) AF: 0.866 AC: 4183 AN: 4830

European-Finnish (FIN) AF: 0.800 AC: 8451 AN: 10570

Middle Eastern (MID) AF: 0.803 AC: 236 AN: 294

European-Non Finnish (NFE) AF: 0.865 AC: 58832 AN: 68008

Other (OTH) AF: 0.847 AC: 1789 AN: 2112

Alfa AF: 0.862 Hom.: 84501

Bravo AF: 0.853

Asia WGS AF: 0.870 AC: 3025 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Familial hyperthyroidism due to mutations in TSH receptor (1)
-	-	1	Hypothyroidism due to TSH receptor mutations (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.14
DANN	Benign	0.35
PhyloP100		-0.36
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs7144481;

hg19: chr14-81610942;