rs74315377

Variant names:

• chr1-168291339-C-T
• rs74315377
• NM_005149.3:c.383C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_005149.3(TBX19):​c.383C>T​(p.Ser128Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000684 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: 0.0000068 (0 hom.)
• Consequence: TBX19 NM_005149.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.46
• Publications: 6 publications found

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]

TBX19 Gene-Disease associations (from GenCC):

• congenital isolated adrenocorticotropic hormone deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a DNA_binding_region T-box (size 173) in uniprot entity TBX19_HUMAN there are 6 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, 0.992
• PP5: Variant 1-168291339-C-T is Pathogenic according to our data. Variant chr1-168291339-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 5441.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005149.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX19	NM_005149.3	MANE Select	c.383C>T	p.Ser128Phe	missense	Exon 2 of 8	NP_005140.1	O60806

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX19	ENST00000367821.8	TSL:1 MANE Select	c.383C>T	p.Ser128Phe	missense	Exon 2 of 8	ENSP00000356795.3	O60806
	TBX19	ENST00000431969.5	TSL:5	c.179C>T	p.Ser60Phe	missense	Exon 1 of 6	ENSP00000397540.1	H0Y5A7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251410 AF XY: 0.00000736

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461892 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000809 AC: 9 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000824 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Congenital isolated adrenocorticotropic hormone deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		7.5
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-6.0	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.96		Loss of disorder (P = 0.0432)
MVP		0.99
MPC		0.95
ClinPred		1.0	D
GERP RS		5.5
PromoterAI		-0.0038	Neutral
Varity_R		0.96
gMVP		0.84
Mutation Taster		=5/95	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs74315377; hg19: chr1-168260577;