Genetic Variant TSHR:c.-60G>A (chr14-80955621-G-A) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_000369.5(TSHR):c.-60G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000315 in 1,604,256 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00031 ( 1 hom. )

Consequence

TSHR
NM_000369.5 5_prime_UTR

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.241

Publications

1 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.56).

BP6

Variant 14-80955621-G-A is Benign according to our data. Variant chr14-80955621-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 314689.

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.000312 (453/1451936) while in subpopulation EAS AF = 0.00356 (141/39656). AF 95% confidence interval is 0.00308. There are 1 homozygotes in GnomAdExome4. There are 226 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position passed quality control check.

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	UniProt
TSHR	NM_000369.5	MANE Select	c.-60G>A	5_prime_UTR	Exon 1 of 10	NP_000360.2	P16473-1
TSHR	NM_001142626.3		c.-60G>A	5_prime_UTR	Exon 1 of 9	NP_001136098.1	P16473-3
TSHR	NM_001018036.3		c.-60G>A	5_prime_UTR	Exon 1 of 9	NP_001018046.1	P16473-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TSHR	ENST00000298171.7	TSL:1 MANE Select	c.-60G>A	5_prime_UTR	Exon 1 of 10	ENSP00000298171.2	P16473-1
TSHR	ENST00000342443.10	TSL:1	c.-60G>A	5_prime_UTR	Exon 1 of 9	ENSP00000340113.6	P16473-2
CEP128	ENST00000555529.5	TSL:1	c.-172+2557C>T	intron	N/A	ENSP00000451137.1	Q86TS1

Frequencies

GnomAD3 genomes

AF:

0.000348

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00232

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00122

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.000478

GnomAD4 exome

AF:

0.000312

AC:

453

AN:

1451936

Hom.:

Cov.:

AF XY:

0.000313

AC XY:

226

AN XY:

722780

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33256

American (AMR)

AF:

0.0000224

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00165

AC:

AN:

26086

East Asian (EAS)

AF:

0.00356

AC:

141

AN:

39656

South Asian (SAS)

AF:

0.000291

AC:

AN:

85778

European-Finnish (FIN)

AF:

0.000752

AC:

AN:

53168

Middle Eastern (MID)

AF:

0.000459

AC:

AN:

4358

European-Non Finnish (NFE)

AF:

0.000150

AC:

166

AN:

1104978

Other (OTH)

AF:

0.000584

AC:

AN:

59940

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

119

149

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:

0.000348

AC:

AN:

152320

Hom.:

Cov.:

AF XY:

0.000362

AC XY:

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41570

American (AMR)

AF:

0.00

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3472

East Asian (EAS)

AF:

0.00232

AC:

AN:

5166

South Asian (SAS)

AF:

0.000414

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00122

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000265

AC:

AN:

68024

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000424

Hom.:

Bravo

AF:

0.000298

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Familial hyperthyroidism due to mutations in TSH receptor (1)

Hypothyroidism due to TSH receptor mutations (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

6.4

(source)

DANN

Benign

0.87

PhyloP100

0.24

PromoterAI

0.0060

Neutral

(source)

Mutation Taster

=299/1

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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