rs200197424

chr1-168293210-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_005149.3(TBX19):c.535C>T(p.Arg179Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000471 in 1,613,534 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000049 (0 hom.)
• Consequence: TBX19 NM_005149.3 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 3.91

Genes affected

TBX19 (HGNC:11596): (T-box transcription factor 19) This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processes. Mutations in this gene were found in patients with isolated deficiency of pituitary POMC-derived ACTH, suggesting an essential role for this gene in differentiation of the pituitary POMC lineage. ACTH deficiency is characterized by adrenal insufficiency symptoms such as weight loss, lack of appetite (anorexia), weakness, nausea, vomiting, and low blood pressure. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-168293210-C-T is Pathogenic according to our data. Variant chr1-168293210-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 293458.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=2}. Variant chr1-168293210-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX19	NM_005149.3	c.535C>T	p.Arg179Ter	stop_gained	3/8	ENST00000367821.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX19	ENST00000367821.8	c.535C>T	p.Arg179Ter	stop_gained	3/8	1	NM_005149.3	P1
TBX19	ENST00000431969.5	c.334C>T	p.Arg112Ter	stop_gained	2/6	5

Frequencies

GnomAD3 genomes AF: 0.0000330 AC: 5 AN: 151698 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000557 AC: 14 AN: 251378 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135864

Gnomad AFR exome AF: 0.0000615

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: 0.0000880

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000486 AC: 71 AN: 1461718 Hom.: 0 Cov.: 58 AF XY: 0.0000509 AC XY: 37 AN XY: 727160

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.0000585

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 151816 Hom.: 0 Cov.: 31 AF XY: 0.0000270 AC XY: 2 AN XY: 74176

Gnomad4 AFR AF: 0.0000242

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: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000124 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000412 AC: 5

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2023	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 15613420, 31589614, 33423260, 33098107, 12651888) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 15, 2022	This sequence change creates a premature translational stop signal (p.Arg179*) in the TBX19 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TBX19 are known to be pathogenic (PMID: 22170728). This variant is present in population databases (rs200197424, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with isolated adrenocorticotropic hormone deficiency (PMID: 12651888, 33423260). ClinVar contains an entry for this variant (Variation ID: 293458). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Congenital isolated adrenocorticotropic hormone deficiency Pathogenic:1 Uncertain:1

Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	May 28, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Nov 13, 2017	The TBX19 c.535C>T (p.Arg179Ter) is a stop-gained variant that is predicted to result in premature termination of the protein. The p.Arg179Ter variant has been reported in a single study in which it was identified in a homozygous state in one individual with neonatal onset ACTH deficiency and in a heterozygous state in the unaffected consanguineous parents (Pulichino et al. 2003). Control data are unavailable for this variant, which is reported at a frequency of 0.00004 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence and potential impact of stop-gained variants, the p.Arg179Ter variant is classified as a variant of unknown significance, but suspicious for pathogenicity, for ACTH deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.59
Cadd	Pathogenic	38
Dann	Uncertain	1.0
Eigen	Pathogenic	0.81
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.86	D
MutationTaster	Benign	1.0	A
Vest4		0.89
ClinPred		0.85	D
GERP RS		4.1

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: rs200197424; hg19: chr1-168262448;