rs755485552

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_000549.5(TSHB):c.373delT(p.Cys125ValfsTer10) variant causes a frameshift change. The variant allele was found at a frequency of 0.000332 in 1,613,702 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00035 ( 1 hom. )

Consequence

TSHB
NM_000549.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 5.94

Variant links:

Genes affected

TSHB (HGNC:12372): (thyroid stimulating hormone subunit beta) The four human glycoprotein hormones chorionic gonadotropin (CG), luteinizing hormone (LH), follicle stimulating hormone (FSH), and thyroid stimulating hormone (TSH) are dimers consisting of alpha and beta subunits that are associated noncovalently. The alpha subunits of these hormones are identical, however, their beta chains are unique and confer biological specificity. Thyroid stimulating hormone functions in the control of thyroid structure and metabolism. The protein encoded by this gene is the beta subunit of thyroid stimulating hormone. Mutations in this gene are associated with congenital central and secondary hypothyroidism and Hashimoto's thyroiditis. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2013]

TSHB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.106 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-115034182-CT-C is Pathogenic according to our data. Variant chr1-115034182-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 437070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-115034182-CT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSHB	NM_000549.5 link	c.373delT	p.Cys125ValfsTer10	frameshift_variant	Exon 3 of 3	ENST00000256592.3	NP_000540.2	P01222-1
TSHB	NM_001277991.1 link	c.238delT	p.Cys80ValfsTer10	frameshift_variant	Exon 1 of 1		NP_001264920.1	P01222-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSHB	ENST00000256592.3 link	c.373delT	p.Cys125ValfsTer10	frameshift_variant	Exon 3 of 3	5	NM_000549.5	ENSP00000256592.1		P01222-1

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000163

AC:

AN:

251170

Hom.:

AF XY:

0.000184

AC XY:

AN XY:

135746

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000343

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000350

AC:

512

AN:

1461546

Hom.:

Cov.:

AF XY:

0.000347

AC XY:

252

AN XY:

727088

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.000444

Gnomad4 OTH exome

AF:

0.000215

GnomAD4 genome

AF:

0.000158

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000309

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.000162

EpiCase

AF:

0.000164

EpiControl

AF:

0.000296

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Isolated thyroid-stimulating hormone deficiency

Pathogenic:4

May 08, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 15, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 15, 2022

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PM3_Strong -

not provided

Pathogenic:2

Mar 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Cys125Valfs*10) in the TSHB gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 14 amino acid(s) of the TSHB protein. This variant is present in population databases (rs755485552, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with clinical features of congenital hypothyroidism (PMID: 8636437, 15297803, 22606512, 27362444, 31166470). It has also been observed to segregate with disease in related individuals. This variant is also known as C105V or 313delT. ClinVar contains an entry for this variant (Variation ID: 437070). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects TSHB function (PMID: 8636437). For these reasons, this variant has been classified as Pathogenic. -

Sep 26, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect as c.373delT is shown to be biologically inactive (PMID: 8636437); Frameshift variant predicted to result in abnormal protein length as the last 14 amino acids are replaced with 9 different amino acids; This variant is associated with the following publications: (PMID: 8636437, 22606512, 27362444, 31166470, 31703413, 31980526, 31384098, 15297803, 31589614, 36001021, 34780050) -

Pituitary hypothyroidism

Pathogenic:1

Dec 28, 2021

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

DNA sequence analysis of the TSHB gene demonstrated a single base pair deletion in exon 3, c.373del. This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon 10 amino acids downstream of the change, p.Cys125Valfs*10. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated TSHB protein with potentially abnormal function. This sequence change has been described in the gnomAD database with a frequency of o.031% in the non-Finnish European subpopulation (dbSNP rs755485552). This pathogenic sequence change has previously been described in the homozygous and compound heterozygous state in multiple individuals with TSHB-related hypothyroidism (PMID: 31166470, 22606512, 31703413, 15297803, 27362444). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over