1-168281070-G-T

Variant names:

• chr1-168281070-G-T
• rs187423054
• NM_005149.3:c.-21G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005149.3(TBX19):​c.-21G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,304 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TBX19 NM_005149.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0210
• Publications: 0 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: PanelApp Australia, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).

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.-21G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	NP_005140.1	O60806
	TBX19	NM_005149.3	MANE Select	c.-21G>T		5_prime_UTR	Exon 1 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.-21G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	ENSP00000356795.3	O60806
	TBX19	ENST00000367821.8	TSL:1 MANE Select	c.-21G>T		5_prime_UTR	Exon 1 of 8	ENSP00000356795.3	O60806

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461304 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726968

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86080

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111780

Other (OTH) AF: 0.00 AC: 0 AN: 60380

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.23
DANN	Benign	0.79
PhyloP100		0.021
PromoterAI		-0.022	Neutral

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs187423054;

hg19: chr1-168250308;