1-168304963-G-A

Variant names:

• chr1-168304963-G-A
• rs4656579
• NM_005149.3:c.728-45G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005149.3(TBX19):​c.728-45G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.663 in 1,592,222 control chromosomes in the GnomAD database, including 357,890 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.61 (28832 hom., cov: 32)
  • Exomes 𝑓: 0.67 (329058 hom.)
• Consequence: TBX19 NM_005149.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.642
• Publications: 8 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 1-168304963-G-A is Benign according to our data. Variant chr1-168304963-G-A is described in ClinVar as Benign. ClinVar VariationId is 1334932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.702 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX19	NM_005149.3	MANE Select	c.728-45G>A		intron	N/A	NP_005140.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX19	ENST00000367821.8	TSL:1 MANE Select	c.728-45G>A		intron	N/A	ENSP00000356795.3
	TBX19	ENST00000431969.5	TSL:5	c.524-3779G>A		intron	N/A	ENSP00000397540.1
	TBX19	ENST00000441464.1	TSL:2	c.224-45G>A		intron	N/A	ENSP00000390731.1

Frequencies

GnomAD3 genomes AF: 0.605 AC: 91957 AN: 151944 Hom.: 28810 Cov.: 32

Gnomad AFR AF: 0.487

Gnomad AMI AF: 0.767

Gnomad AMR AF: 0.599

Gnomad ASJ AF: 0.652

Gnomad EAS AF: 0.346

Gnomad SAS AF: 0.424

Gnomad FIN AF: 0.602

Gnomad MID AF: 0.601

Gnomad NFE AF: 0.707

Gnomad OTH AF: 0.606

GnomAD2 exomes AF: 0.603 AC: 148695 AN: 246620 AF XY: 0.602

Gnomad AFR exome AF: 0.476

Gnomad AMR exome AF: 0.583

Gnomad ASJ exome AF: 0.665

Gnomad EAS exome AF: 0.340

Gnomad FIN exome AF: 0.614

Gnomad NFE exome AF: 0.705

Gnomad OTH exome AF: 0.629

GnomAD4 exome AF: 0.669 AC: 963900 AN: 1440160 Hom.: 329058 Cov.: 27 AF XY: 0.664 AC XY: 476576 AN XY: 717862

African (AFR) AF: 0.482 AC: 15971 AN: 33110

American (AMR) AF: 0.583 AC: 26030 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.663 AC: 17241 AN: 26016

East Asian (EAS) AF: 0.377 AC: 14923 AN: 39596

South Asian (SAS) AF: 0.448 AC: 38473 AN: 85832

European-Finnish (FIN) AF: 0.623 AC: 31431 AN: 50416

Middle Eastern (MID) AF: 0.585 AC: 3279 AN: 5606

European-Non Finnish (NFE) AF: 0.711 AC: 778460 AN: 1095186

Other (OTH) AF: 0.638 AC: 38092 AN: 59746

GnomAD4 genome AF: 0.605 AC: 92022 AN: 152062 Hom.: 28832 Cov.: 32 AF XY: 0.594 AC XY: 44118 AN XY: 74332

African (AFR) AF: 0.487 AC: 20189 AN: 41480

American (AMR) AF: 0.598 AC: 9143 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.652 AC: 2257 AN: 3464

East Asian (EAS) AF: 0.347 AC: 1794 AN: 5174

South Asian (SAS) AF: 0.424 AC: 2040 AN: 4812

European-Finnish (FIN) AF: 0.602 AC: 6354 AN: 10560

Middle Eastern (MID) AF: 0.599 AC: 176 AN: 294

European-Non Finnish (NFE) AF: 0.707 AC: 48085 AN: 67972

Other (OTH) AF: 0.609 AC: 1289 AN: 2116

Alfa AF: 0.674 Hom.: 77743

Bravo AF: 0.601

Asia WGS AF: 0.421 AC: 1465 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Congenital isolated adrenocorticotropic hormone deficiency Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.1
DANN	Benign	0.36
PhyloP100		-0.64
Mutation Taster		=100/0	polymorphism (auto)

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: rs4656579; hg19: chr1-168274201; COSMIC: COSV63198712; COSMIC: COSV63198712;