rs755485552

Positions:

• chr1-115034182-CT-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000549.5(TSHB):​c.373delT​(p.Cys125fs) 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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 5.94

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]

ACMG classification

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/exons	MANE	Protein	UniProt
TSHB	NM_000549.5	c.373delT	p.Cys125fs	frameshift_variant	3/3	ENST00000256592.3	NP_000540.2
TSHB	NM_001277991.1	c.238delT	p.Cys80fs	frameshift_variant	1/1		NP_001264920.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSHB	ENST00000256592.3	c.373delT	p.Cys125fs	frameshift_variant	3/3	5	NM_000549.5	ENSP00000256592.1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152156 Hom.: 0 Cov.: 32

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: 41 AN: 251170 Hom.: 0 AF XY: 0.000184 AC XY: 25 AN XY: 135746

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.: 1 Cov.: 32 AF XY: 0.000347 AC XY: 252 AN XY: 727088

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: 24 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10 AN XY: 74334

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.: 0

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

Submissions by phenotype

Isolated thyroid-stimulating hormone deficiency Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Nov 15, 2022	PS3, PM3_Strong -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 15, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 08, 2024	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 09, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 26, 2024	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

Pathogenic, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 28, 2021

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

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

Other links and lift over

dbSNP: rs755485552; hg19: chr1-115576803;