Genetic Variant TSHR:c.170+1924T>G (chr14-80957774-T-G) – 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+1924T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.499 in 152,098 control chromosomes in the GnomAD database, including 20,489 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 0.50 ( 20487 hom., cov: 32)

Exomes 𝑓: 0.38 ( 2 hom. )

Consequence

TSHR
NM_000369.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.43

Publications

8 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:

CEP128 (HGNC:20359): (centrosomal protein 128) Involved in protein localization. Located in centriole and spindle pole. Part of centriolar subdistal appendage. [provided by Alliance of Genome Resources, Apr 2022]

CEP128 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=-0.84).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.7 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSHR	NM_000369.5 link	c.170+1924T>G		intron_variant	Intron 1 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.170+1924T>G		intron_variant	Intron 1 of 9	1	NM_000369.5	ENSP00000298171.2		A0A0A0MTJ0

Frequencies

GnomAD3 genomes

AF:

0.499

AC:

75788

AN:

151956

Hom.:

20457

Cov.:

show subpopulations

Gnomad AFR

AF:

0.707

Gnomad AMI

AF:

0.557

Gnomad AMR

AF:

0.447

Gnomad ASJ

AF:

0.545

Gnomad EAS

AF:

0.223

Gnomad SAS

AF:

0.501

Gnomad FIN

AF:

0.309

Gnomad MID

AF:

0.558

Gnomad NFE

AF:

0.431

Gnomad OTH

AF:

0.495

GnomAD4 exome

AF:

0.375

AC:

AN:

Hom.:

Cov.:

AF XY:

0.409

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.500

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.500

AC:

AN:

Middle Eastern (MID)

AF:

0.500

AC:

AN:

European-Non Finnish (NFE)

AF:

0.167

AC:

AN:

Other (OTH)

AF:

0.667

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.499

AC:

75864

AN:

152074

Hom.:

20487

Cov.:

AF XY:

0.490

AC XY:

36412

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.707

AC:

29286

AN:

41450

American (AMR)

AF:

0.447

AC:

6839

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.545

AC:

1891

AN:

3470

East Asian (EAS)

AF:

0.223

AC:

1154

AN:

5182

South Asian (SAS)

AF:

0.501

AC:

2411

AN:

4814

European-Finnish (FIN)

AF:

0.309

AC:

3265

AN:

10580

Middle Eastern (MID)

AF:

0.541

AC:

157

AN:

290

European-Non Finnish (NFE)

AF:

0.431

AC:

29315

AN:

67980

Other (OTH)

AF:

0.491

AC:

1039

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1860

3720

5580

7440

9300

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

658

1316

1974

2632

3290

<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:

0.474

Hom.:

2773

Bravo

AF:

0.521

Asia WGS

AF:

0.407

AC:

1418

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

7.2

(source)

DANN

Benign

0.60

PhyloP100

2.4

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over