14-81108343-TTCTC-TTCTCTCTCTCTCTC

Variant names:

• chr14-81108343-T-TTCTCTCTCTC
• rs3837640
• NM_000369.5:c.615-28_615-19dupCTCTCTCTCT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000369.5(TSHR):​c.615-28_615-19dupCTCTCTCTCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000792 in 1,262,822 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 7.9e-7 (0 hom.)
• Consequence: TSHR NM_000369.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.247
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSHR	NM_000369.5	c.615-28_615-19dupCTCTCTCTCT		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_615-31insTCTCTCTCTC		intron_variant	Intron 7 of 9	1	NM_000369.5	ENSP00000298171.2

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 7.92e-7 AC: 1 AN: 1262822 Hom.: 0 Cov.: 24 AF XY: 0.00000157 AC XY: 1 AN XY: 635606

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 29480

American (AMR) AF: 0.00 AC: 0 AN: 42364

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23748

East Asian (EAS) AF: 0.00 AC: 0 AN: 38352

South Asian (SAS) AF: 0.00 AC: 0 AN: 78228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50832

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4164

European-Non Finnish (NFE) AF: 0.00000106 AC: 1 AN: 942646

Other (OTH) AF: 0.00 AC: 0 AN: 53008

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.25

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;