14-81143435-G-A

Variant names:

• chr14-81143435-G-A
• rs113951800
• NM_000369.5:c.1377G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000369.5(TSHR):​c.1377G>A​(p.Ala459Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0215 in 1,614,086 control chromosomes in the GnomAD database, including 470 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A459A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.016 (30 hom., cov: 32)
  • Exomes 𝑓: 0.022 (440 hom.)
• Consequence: TSHR NM_000369.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.88
• 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

ENSG00000284959 (HGNC:58172):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 14-81143435-G-A is Benign according to our data. Variant chr14-81143435-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255951.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.88 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0157 (2389/152198) while in subpopulation SAS AF = 0.0428 (206/4818). AF 95% confidence interval is 0.038. There are 30 homozygotes in GnomAd4. There are 1181 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 30 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSHR	NM_000369.5	c.1377G>A	p.Ala459Ala	synonymous_variant	Exon 10 of 10	ENST00000298171.7	NP_000360.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSHR	ENST00000298171.7	c.1377G>A	p.Ala459Ala	synonymous_variant	Exon 10 of 10	1	NM_000369.5	ENSP00000298171.2

Frequencies

GnomAD3 genomes AF: 0.0157 AC: 2388 AN: 152080 Hom.: 30 Cov.: 32

Gnomad AFR AF: 0.00459

Gnomad AMI AF: 0.0473

Gnomad AMR AF: 0.0104

Gnomad ASJ AF: 0.0207

Gnomad EAS AF: 0.000965

Gnomad SAS AF: 0.0423

Gnomad FIN AF: 0.0141

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0225

Gnomad OTH AF: 0.0139

GnomAD2 exomes AF: 0.0181 AC: 4563 AN: 251460 AF XY: 0.0200

Gnomad AFR exome AF: 0.00418

Gnomad AMR exome AF: 0.00714

Gnomad ASJ exome AF: 0.0174

Gnomad EAS exome AF: 0.000815

Gnomad FIN exome AF: 0.0140

Gnomad NFE exome AF: 0.0210

Gnomad OTH exome AF: 0.0181

GnomAD4 exome AF: 0.0221 AC: 32240 AN: 1461888 Hom.: 440 Cov.: 31 AF XY: 0.0226 AC XY: 16452 AN XY: 727246

African (AFR) AF: 0.00457 AC: 153 AN: 33480

American (AMR) AF: 0.00758 AC: 339 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0185 AC: 483 AN: 26136

East Asian (EAS) AF: 0.000982 AC: 39 AN: 39700

South Asian (SAS) AF: 0.0404 AC: 3488 AN: 86258

European-Finnish (FIN) AF: 0.0129 AC: 687 AN: 53414

Middle Eastern (MID) AF: 0.0354 AC: 204 AN: 5768

European-Non Finnish (NFE) AF: 0.0230 AC: 25608 AN: 1112012

Other (OTH) AF: 0.0205 AC: 1239 AN: 60396

GnomAD4 genome AF: 0.0157 AC: 2389 AN: 152198 Hom.: 30 Cov.: 32 AF XY: 0.0159 AC XY: 1181 AN XY: 74400

African (AFR) AF: 0.00460 AC: 191 AN: 41524

American (AMR) AF: 0.0104 AC: 159 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0207 AC: 72 AN: 3472

East Asian (EAS) AF: 0.000967 AC: 5 AN: 5168

South Asian (SAS) AF: 0.0428 AC: 206 AN: 4818

European-Finnish (FIN) AF: 0.0141 AC: 149 AN: 10602

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0225 AC: 1532 AN: 67998

Other (OTH) AF: 0.0137 AC: 29 AN: 2114

Alfa AF: 0.0157 Hom.: 10

Bravo AF: 0.0145

Asia WGS AF: 0.0190 AC: 65 AN: 3478

EpiCase AF: 0.0230

EpiControl AF: 0.0225

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 19, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TSHR p.Ala459Ala variant was identified in 5 of 194 proband chromosomes (frequency: 0.0258) from individuals with primary congenital hypothyroidism or autonomously functioning thyroid nodules (Alves_2010_PMID:21714466; Gabriel_1999_PMID:10487707). In a case study, the TSHR gene was sequenced in a girl with severe non-autoimmune hyperthyroidism and her mother with autoimmune thyroid disease; the mother was found to carry the p.A459A variant but it was not present in the girl (Scaglia_2012_PMID:23295291). The variant was identified in dbSNP (ID: rs113951800), ClinVar (classified as likely benign by Illumina and as benign by PreventionGenetics) and LOVD 3.0 (classified as benign) but was not identified in Cosmic. The variant was identified in control databases in 4983 of 282856 chromosomes (63 homozygous) at a frequency of 0.017617 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 1259 of 30616 chromosomes (freq: 0.04112), European (non-Finnish) in 2690 of 129178 chromosomes (freq: 0.02082), Ashkenazi Jewish in 184 of 10370 chromosomes (freq: 0.01774), Other in 126 of 7224 chromosomes (freq: 0.01744), European (Finnish) in 344 of 25112 chromosomes (freq: 0.0137), Latino in 256 of 35440 chromosomes (freq: 0.007223), African in 108 of 24966 chromosomes (freq: 0.004326), and East Asian in 16 of 19950 chromosomes (freq: 0.000802). The p.Ala459Ala variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. However, four of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing and the creation of a new 3' splice site. However, this has not been confirmed through RNA analysis and is not predictive enough to assume pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

Hypothyroidism due to TSH receptor mutations Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Familial hyperthyroidism due to mutations in TSH receptor Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.66
DANN	Benign	0.75
PhyloP100		-2.9
Mutation Taster		=99/1	polymorphism (auto)

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: rs113951800; hg19: chr14-81609779;