14-81108343-TTCTC-TTCTCTCTC

Variant names:

• chr14-81108343-T-TTCTC
• rs3837640
• NM_000369.5:c.615-22_615-19dupCTCT

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The NM_000369.5(TSHR):​c.615-22_615-19dupCTCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.557 in 1,408,358 control chromosomes in the GnomAD database, including 184,930 homozygotes. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.63 (29959 hom., cov: 0)
  • Exomes 𝑓: 0.55 (154971 hom.)
• Consequence: TSHR NM_000369.5 intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.247
• Publications: 3 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 -9 ACMG points.

• BP6: Variant 14-81108343-T-TTCTC is Benign according to our data. Variant chr14-81108343-T-TTCTC is described in ClinVar as Likely_benign. ClinVar VariationId is 255954.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.702 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSHR	NM_000369.5	c.615-22_615-19dupCTCT		intron_variant	Intron 7 of 9	ENST00000298171.7	NP_000360.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSHR	ENST00000298171.7	c.615-32_615-31insTCTC		intron_variant	Intron 7 of 9	1	NM_000369.5	ENSP00000298171.2

Frequencies

GnomAD3 genomes AF: 0.627 AC: 94591 AN: 150778 Hom.: 29950 Cov.: 0

Gnomad AFR AF: 0.620

Gnomad AMI AF: 0.430

Gnomad AMR AF: 0.620

Gnomad ASJ AF: 0.745

Gnomad EAS AF: 0.350

Gnomad SAS AF: 0.722

Gnomad FIN AF: 0.646

Gnomad MID AF: 0.719

Gnomad NFE AF: 0.640

Gnomad OTH AF: 0.652

GnomAD2 exomes AF: 0.530 AC: 102414 AN: 193136 AF XY: 0.531

Gnomad AFR exome AF: 0.536

Gnomad AMR exome AF: 0.538

Gnomad ASJ exome AF: 0.599

Gnomad EAS exome AF: 0.293

Gnomad FIN exome AF: 0.570

Gnomad NFE exome AF: 0.544

Gnomad OTH exome AF: 0.554

GnomAD4 exome AF: 0.549 AC: 690441 AN: 1257464 Hom.: 154971 Cov.: 24 AF XY: 0.550 AC XY: 348348 AN XY: 633040

African (AFR) AF: 0.534 AC: 15685 AN: 29376

American (AMR) AF: 0.550 AC: 23247 AN: 42242

Ashkenazi Jewish (ASJ) AF: 0.611 AC: 14482 AN: 23698

East Asian (EAS) AF: 0.338 AC: 12949 AN: 38288

South Asian (SAS) AF: 0.595 AC: 46409 AN: 78028

European-Finnish (FIN) AF: 0.565 AC: 28660 AN: 50738

Middle Eastern (MID) AF: 0.615 AC: 2547 AN: 4142

European-Non Finnish (NFE) AF: 0.552 AC: 517712 AN: 938156

Other (OTH) AF: 0.545 AC: 28750 AN: 52796

GnomAD4 genome AF: 0.627 AC: 94647 AN: 150894 Hom.: 29959 Cov.: 0 AF XY: 0.624 AC XY: 45999 AN XY: 73680

African (AFR) AF: 0.620 AC: 25485 AN: 41096

American (AMR) AF: 0.619 AC: 9386 AN: 15154

Ashkenazi Jewish (ASJ) AF: 0.745 AC: 2567 AN: 3444

East Asian (EAS) AF: 0.350 AC: 1799 AN: 5142

South Asian (SAS) AF: 0.723 AC: 3445 AN: 4768

European-Finnish (FIN) AF: 0.646 AC: 6664 AN: 10310

Middle Eastern (MID) AF: 0.719 AC: 207 AN: 288

European-Non Finnish (NFE) AF: 0.640 AC: 43339 AN: 67682

Other (OTH) AF: 0.650 AC: 1364 AN: 2100

Alfa AF: 0.500 Hom.: 1613

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

TSHR-related disorder Benign:1

May 01, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.25
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3837640; hg19: chr14-81574687; COSMIC: COSV107314903; COSMIC: COSV107314903;