rs74315378

chr1-168291213-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_005149.3(TBX19):c.257T>G(p.Met86Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,892 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 Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TBX19 NM_005149.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.57

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a DNA_binding_region T-box (size 173) in uniprot entity TBX19_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_005149.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.962
• PP5: Variant 1-168291213-T-G is Pathogenic according to our data. Variant chr1-168291213-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 5442.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX19	NM_005149.3	c.257T>G	p.Met86Arg	missense_variant	2/8	ENST00000367821.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX19	ENST00000367821.8	c.257T>G	p.Met86Arg	missense_variant	2/8	1	NM_005149.3	P1
TBX19	ENST00000431969.5	c.56T>G	p.Met19Arg	missense_variant	1/6	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461892 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Congenital isolated adrenocorticotropic hormone deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2007

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Pathogenic	28
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.76	D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.72	T
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	-0.049	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.84
Sift	Benign	0.072	T
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.84		Loss of stability (P = 0.072);
MVP		0.92
MPC		1.1
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.89
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs74315378; hg19: chr1-168260451;