Genetic Variant TSHR:c.170+26317G>A (chr14-80982167-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000369.5(TSHR):c.170+26317G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.296 in 571,004 control chromosomes in the GnomAD database, including 27,178 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.27 ( 6437 hom., cov: 32)

Exomes 𝑓: 0.31 ( 20741 hom. )

Consequence

TSHR
NM_000369.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.365

Publications

9 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 links:

GPRASP3P1 (HGNC:51373): (GPRASP3 pseudogene 1)

GPRASP3P1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.362 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
TSHR	NM_000369.5	MANE Select	c.170+26317G>A	intron	N/A	NP_000360.2
TSHR	NM_001142626.3		c.170+26317G>A	intron	N/A	NP_001136098.1
TSHR	NM_001018036.3		c.170+26317G>A	intron	N/A	NP_001018046.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
TSHR	ENST00000298171.7	TSL:1 MANE Select	c.170+26317G>A	intron	N/A	ENSP00000298171.2
TSHR	ENST00000554435.1	TSL:1	c.170+26317G>A	intron	N/A	ENSP00000450549.1
TSHR	ENST00000342443.10	TSL:1	c.170+26317G>A	intron	N/A	ENSP00000340113.6

Frequencies

GnomAD3 genomes

AF:

0.270

AC:

40982

AN:

152002

Hom.:

6433

Cov.:

show subpopulations

Gnomad AFR

AF:

0.110

Gnomad AMI

AF:

0.430

Gnomad AMR

AF:

0.328

Gnomad ASJ

AF:

0.334

Gnomad EAS

AF:

0.199

Gnomad SAS

AF:

0.376

Gnomad FIN

AF:

0.303

Gnomad MID

AF:

0.199

Gnomad NFE

AF:

0.341

Gnomad OTH

AF:

0.286

GnomAD4 exome

AF:

0.306

AC:

128219

AN:

418884

Hom.:

20741

Cov.:

AF XY:

0.306

AC XY:

69566

AN XY:

227218

show subpopulations

African (AFR)

AF:

0.0975

AC:

1188

AN:

12190

American (AMR)

AF:

0.382

AC:

9647

AN:

25278

Ashkenazi Jewish (ASJ)

AF:

0.290

AC:

3165

AN:

10912

East Asian (EAS)

AF:

0.214

AC:

4979

AN:

23310

South Asian (SAS)

AF:

0.337

AC:

13596

AN:

40334

European-Finnish (FIN)

AF:

0.308

AC:

12098

AN:

39272

Middle Eastern (MID)

AF:

0.205

AC:

644

AN:

3138

European-Non Finnish (NFE)

AF:

0.315

AC:

76354

AN:

242260

Other (OTH)

AF:

0.295

AC:

6548

AN:

22190

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

3568

7136

10704

14272

17840

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

604

1208

1812

2416

3020

<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:

0.270

AC:

41002

AN:

152120

Hom.:

6437

Cov.:

AF XY:

0.269

AC XY:

19980

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.110

AC:

4570

AN:

41538

American (AMR)

AF:

0.328

AC:

5017

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.334

AC:

1159

AN:

3468

East Asian (EAS)

AF:

0.199

AC:

1031

AN:

5170

South Asian (SAS)

AF:

0.376

AC:

1812

AN:

4820

European-Finnish (FIN)

AF:

0.303

AC:

3197

AN:

10566

Middle Eastern (MID)

AF:

0.190

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.341

AC:

23171

AN:

67958

Other (OTH)

AF:

0.283

AC:

598

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1438

2876

4314

5752

7190

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

438

876

1314

1752

2190

<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:

0.231

Hom.:

1476

Bravo

AF:

0.265

Asia WGS

AF:

0.295

AC:

1029

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

3.0

(source)

DANN

Benign

0.40

PhyloP100

0.36

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over