ENST00000554263.5:c.*45T>C

Variant names:

• chr14-81108501-T-C
• rs28636074
• ENST00000554263.5:c.*45T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000554263.5(TSHR):​c.*45T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.02 in 1,505,526 control chromosomes in the GnomAD database, including 521 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (26 hom., cov: 25)
  • Exomes 𝑓: 0.021 (495 hom.)
• Consequence: TSHR ENST00000554263.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0880
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 14-81108501-T-C is Benign according to our data. Variant chr14-81108501-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 403571.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0143 (2088/146066) while in subpopulation NFE AF = 0.0214 (1427/66558). AF 95% confidence interval is 0.0205. There are 26 homozygotes in GnomAd4. There are 966 alleles in the male GnomAd4 subpopulation. Median coverage is 25. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 26 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000554263.5. 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+49T>C		intron	N/A	NP_000360.2
	TSHR	NM_001142626.3		c.693-48T>C		intron	N/A	NP_001136098.1
	TSHR	NM_001018036.3		c.692+49T>C		intron	N/A	NP_001018046.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSHR	ENST00000554263.5	TSL:1	c.*45T>C		3_prime_UTR	Exon 8 of 8	ENSP00000451202.1
	TSHR	ENST00000298171.7	TSL:1 MANE Select	c.692+49T>C		intron	N/A	ENSP00000298171.2
	TSHR	ENST00000554435.1	TSL:1	c.693-48T>C		intron	N/A	ENSP00000450549.1

Frequencies

GnomAD3 genomes AF: 0.0143 AC: 2088 AN: 146018 Hom.: 26 Cov.: 25

Gnomad AFR AF: 0.00446

Gnomad AMI AF: 0.00111

Gnomad AMR AF: 0.0162

Gnomad ASJ AF: 0.0185

Gnomad EAS AF: 0.000394

Gnomad SAS AF: 0.0100

Gnomad FIN AF: 0.0107

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0214

Gnomad OTH AF: 0.0204

GnomAD4 exome AF: 0.0206 AC: 28014 AN: 1359460 Hom.: 495 Cov.: 34 AF XY: 0.0202 AC XY: 13676 AN XY: 676716

African (AFR) AF: 0.00342 AC: 107 AN: 31260

American (AMR) AF: 0.0109 AC: 425 AN: 38954

Ashkenazi Jewish (ASJ) AF: 0.0239 AC: 580 AN: 24242

East Asian (EAS) AF: 0.000155 AC: 6 AN: 38788

South Asian (SAS) AF: 0.0126 AC: 966 AN: 76424

European-Finnish (FIN) AF: 0.00856 AC: 425 AN: 49648

Middle Eastern (MID) AF: 0.0221 AC: 114 AN: 5164

European-Non Finnish (NFE) AF: 0.0234 AC: 24266 AN: 1038730

Other (OTH) AF: 0.0200 AC: 1125 AN: 56250

GnomAD4 genome AF: 0.0143 AC: 2088 AN: 146066 Hom.: 26 Cov.: 25 AF XY: 0.0136 AC XY: 966 AN XY: 70800

African (AFR) AF: 0.00445 AC: 178 AN: 40036

American (AMR) AF: 0.0162 AC: 238 AN: 14676

Ashkenazi Jewish (ASJ) AF: 0.0185 AC: 63 AN: 3412

East Asian (EAS) AF: 0.000395 AC: 2 AN: 5062

South Asian (SAS) AF: 0.0101 AC: 46 AN: 4568

European-Finnish (FIN) AF: 0.0107 AC: 91 AN: 8538

Middle Eastern (MID) AF: 0.00347 AC: 1 AN: 288

European-Non Finnish (NFE) AF: 0.0214 AC: 1427 AN: 66558

Other (OTH) AF: 0.0202 AC: 41 AN: 2026

Alfa AF: 0.460 Hom.: 8473

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: classification based on high MAF (>1% in 1000Genomes), outside of splice consensus sequence and lack of conservation

Familial gestational hyperthyroidism Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hypothyroidism due to TSH receptor mutations Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Familial hyperthyroidism due to mutations in TSH receptor Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.2
DANN	Benign	0.77
PhyloP100		-0.088
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs28636074; hg19: chr14-81574845; COSMIC: COSV53314966;