chr14-81108343-T-TTC

Variant names:

• chr14-81108343-T-TTC
• rs3837640
• NM_000369.5:c.615-20_615-19dupCT

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_000369.5(TSHR):​c.615-20_615-19dupCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0087 in 1,268,172 control chromosomes in the GnomAD database, including 2 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000073 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0099 (2 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000369.5. 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.615-20_615-19dupCT		intron	N/A	NP_000360.2
	TSHR	NM_001142626.3		c.615-20_615-19dupCT		intron	N/A	NP_001136098.1
	TSHR	NM_001018036.3		c.615-20_615-19dupCT		intron	N/A	NP_001018046.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSHR	ENST00000298171.7	TSL:1 MANE Select	c.615-32_615-31insTC		intron	N/A	ENSP00000298171.2
	TSHR	ENST00000554435.1	TSL:1	c.615-32_615-31insTC		intron	N/A	ENSP00000450549.1
	TSHR	ENST00000342443.10	TSL:1	c.615-32_615-31insTC		intron	N/A	ENSP00000340113.6

Frequencies

GnomAD3 genomes AF: 0.0000730 AC: 11 AN: 150694 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000976

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000195

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000444

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00578 AC: 1117 AN: 193136 AF XY: 0.00593

Gnomad AFR exome AF: 0.00262

Gnomad AMR exome AF: 0.00826

Gnomad ASJ exome AF: 0.0110

Gnomad EAS exome AF: 0.000700

Gnomad FIN exome AF: 0.00476

Gnomad NFE exome AF: 0.00449

Gnomad OTH exome AF: 0.00733

GnomAD4 exome AF: 0.00987 AC: 11024 AN: 1117362 Hom.: 2 Cov.: 24 AF XY: 0.00948 AC XY: 5291 AN XY: 558100

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

African (AFR) AF: 0.00843 AC: 220 AN: 26088

American (AMR) AF: 0.00604 AC: 219 AN: 36280

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 211 AN: 18908

East Asian (EAS) AF: 0.00146 AC: 53 AN: 36364

South Asian (SAS) AF: 0.00923 AC: 567 AN: 61458

European-Finnish (FIN) AF: 0.00475 AC: 209 AN: 43966

Middle Eastern (MID) AF: 0.00973 AC: 35 AN: 3596

European-Non Finnish (NFE) AF: 0.0108 AC: 9102 AN: 844106

Other (OTH) AF: 0.00876 AC: 408 AN: 46596

⚠️ 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 AF: 0.0000729 AC: 11 AN: 150810 Hom.: 0 Cov.: 0 AF XY: 0.0000543 AC XY: 4 AN XY: 73630

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

African (AFR) AF: 0.0000973 AC: 4 AN: 41120

American (AMR) AF: 0.000132 AC: 2 AN: 15166

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3442

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.00 AC: 0 AN: 4774

European-Finnish (FIN) AF: 0.000195 AC: 2 AN: 10242

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

European-Non Finnish (NFE) AF: 0.0000444 AC: 3 AN: 67630

Other (OTH) AF: 0.00 AC: 0 AN: 2096

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0114029), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0823 Hom.: 1613

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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;