Genetic Variant TSHR:c.615-24_615-19dupCTCTCT (chr14-81108343-T-TTCTCTC) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

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

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.247

Publications

3 publications found

Variant links:

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

TSHR links:

ENSG00000284959 (HGNC:58172):

ENSG00000284959 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 link	c.615-24_615-19dupCTCTCT		intron_variant	Intron 7 of 9	ENST00000298171.7	NP_000360.2	P16473A0A0A0MTJ0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSHR	ENST00000298171.7 link	c.615-32_615-31insTCTCTC		intron_variant	Intron 7 of 9	1	NM_000369.5	ENSP00000298171.2		A0A0A0MTJ0

Frequencies

GnomAD3 genomes

AF:

0.00589

AC:

889

AN:

150898

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

Cov.:

AF XY:

0.00882

AC XY:

5601

AN XY:

634878

show subpopulations

African (AFR)

AF:

0.00197

AC:

AN:

29460

American (AMR)

AF:

0.00205

AC:

AN:

42344

Ashkenazi Jewish (ASJ)

AF:

0.00506

AC:

120

AN:

23722

East Asian (EAS)

AF:

0.0000522

AC:

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:

AN:

4164

European-Non Finnish (NFE)

AF:

0.0105

AC:

9922

AN:

941232

Other (OTH)

AF:

0.0104

AC:

550

AN:

52956

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.447

Heterozygous variant carriers

456

912

1369

1825

2281

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

366

732

1098

1464

1830

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00589

AC:

889

AN:

151014

Hom.:

Cov.:

AF XY:

0.00572

AC XY:

422

AN XY:

73750

show subpopulations

African (AFR)

AF:

0.00187

AC:

AN:

41136

American (AMR)

AF:

0.00244

AC:

AN:

15178

Ashkenazi Jewish (ASJ)

AF:

0.00377

AC:

AN:

3446

East Asian (EAS)

AF:

0.000194

AC:

AN:

5144

South Asian (SAS)

AF:

0.00168

AC:

AN:

4776

European-Finnish (FIN)

AF:

0.0114

AC:

118

AN:

10328

Middle Eastern (MID)

AF:

0.00

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.00925

AC:

626

AN:

67708

Other (OTH)

AF:

0.00429

AC:

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

133

178

222

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

(source)

Splicing

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

Publications

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14-81108343-TTCTC-TTCTCTCTCTC

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over