14-81108343-T-TTCTCTC

Variant names:

• chr14-81108343-T-TTCTCTC
• rs3837640
• NM_000369.5:c.615-24_615-19dupCTCTCT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_000369.5(TSHR):​c.615-24_615-19dupCTCTCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00886 in 1,412,210 control chromosomes in the GnomAD database, including 53 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0059 (3 hom., cov: 0)
  • Exomes 𝑓: 0.0092 (50 hom.)
• Consequence: TSHR NM_000369.5 intron
• Clinical Significance: Not reported in ClinVar
• 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 -8 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00589 (889/151014) while in subpopulation NFE AF = 0.00925 (626/67708). AF 95% confidence interval is 0.00865. There are 3 homozygotes in GnomAd4. There are 422 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSHR	NM_000369.5	c.615-24_615-19dupCTCTCT		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_615-31insTCTCTC		intron_variant	Intron 7 of 9	1	NM_000369.5	ENSP00000298171.2

Frequencies

GnomAD3 genomes AF: 0.00589 AC: 889 AN: 150898 Hom.: 3 Cov.: 0

Gnomad AFR AF: 0.00188

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00244

Gnomad ASJ AF: 0.00377

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00167

Gnomad FIN AF: 0.0114

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00924

Gnomad OTH AF: 0.00433

GnomAD2 exomes AF: 0.00771 AC: 1489 AN: 193136 AF XY: 0.00751

Gnomad AFR exome AF: 0.00247

Gnomad AMR exome AF: 0.00195

Gnomad ASJ exome AF: 0.00572

Gnomad EAS exome AF: 0.0000583

Gnomad FIN exome AF: 0.0162

Gnomad NFE exome AF: 0.0113

Gnomad OTH exome AF: 0.00884

GnomAD4 exome AF: 0.00921 AC: 11617 AN: 1261196 Hom.: 50 Cov.: 24 AF XY: 0.00882 AC XY: 5601 AN XY: 634878

African (AFR) AF: 0.00197 AC: 58 AN: 29460

American (AMR) AF: 0.00205 AC: 87 AN: 42344

Ashkenazi Jewish (ASJ) AF: 0.00506 AC: 120 AN: 23722

East Asian (EAS) AF: 0.0000522 AC: 2 AN: 38346

South Asian (SAS) AF: 0.00160 AC: 125 AN: 78158

European-Finnish (FIN) AF: 0.0148 AC: 752 AN: 50814

Middle Eastern (MID) AF: 0.000240 AC: 1 AN: 4164

European-Non Finnish (NFE) AF: 0.0105 AC: 9922 AN: 941232

Other (OTH) AF: 0.0104 AC: 550 AN: 52956

GnomAD4 genome AF: 0.00589 AC: 889 AN: 151014 Hom.: 3 Cov.: 0 AF XY: 0.00572 AC XY: 422 AN XY: 73750

African (AFR) AF: 0.00187 AC: 77 AN: 41136

American (AMR) AF: 0.00244 AC: 37 AN: 15178

Ashkenazi Jewish (ASJ) AF: 0.00377 AC: 13 AN: 3446

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5144

South Asian (SAS) AF: 0.00168 AC: 8 AN: 4776

European-Finnish (FIN) AF: 0.0114 AC: 118 AN: 10328

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.00925 AC: 626 AN: 67708

Other (OTH) AF: 0.00429 AC: 9 AN: 2100

Alfa AF: 0.00590 Hom.: 1613

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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

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;