Genetic Variant NM_005149.3:c.728-45G>A (chr1-168304963-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.642

Publications

8 publications found

Variant links:

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

TBX19 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX19	NM_005149.3 link	c.728-45G>A		intron_variant	Intron 5 of 7	ENST00000367821.8	NP_005140.1	O60806B3KRD9

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
TBX19	ENST00000367821.8 link	c.728-45G>A	intron_variant	Intron 5 of 7	1	NM_005149.3	ENSP00000356795.3	O60806
TBX19	ENST00000431969.5 link	c.524-3779G>A	intron_variant	Intron 4 of 5	5		ENSP00000397540.1	H0Y5A7
TBX19	ENST00000441464.1 link	c.224-45G>A	intron_variant	Intron 2 of 4	2		ENSP00000390731.1	H0Y4B1

Frequencies

GnomAD3 genomes

AF:

0.605

AC:

91957

AN:

151944

Hom.:

28810

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.664

AC XY:

476576

AN XY:

717862

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

16521

33042

49563

66084

82605

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19184

38368

57552

76736

95920

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.605

AC:

92022

AN:

152062

Hom.:

28832

Cov.:

AF XY:

0.594

AC XY:

44118

AN XY:

74332

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1797

3594

5390

7187

8984

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

748

1496

2244

2992

3740

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

LINK: link

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

3.1

(source)

DANN

Benign

0.36

PhyloP100

-0.64

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over