Genetic Variant TBX1:c.1009+4367G>A (chr22-19770369-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000329705.11(TBX1):c.1009+4367G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 152,232 control chromosomes in the GnomAD database, including 3,065 homozygotes. 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: 𝑓 0.17 ( 3065 hom., cov: 33)

Consequence

TBX1
ENST00000329705.11 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.36

Publications

32 publications found

Variant links:

Genes affected

TBX1 (HGNC:11592): (T-box transcription factor 1) 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. This gene product shares 98% amino acid sequence identity with the mouse ortholog. DiGeorge syndrome (DGS)/velocardiofacial syndrome (VCFS), a common congenital disorder characterized by neural-crest-related developmental defects, has been associated with deletions of chromosome 22q11.2, where this gene has been mapped. Studies using mouse models of DiGeorge syndrome suggest a major role for this gene in the molecular etiology of DGS/VCFS. Several alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

TBX1 Gene-Disease associations (from GenCC):

conotruncal heart malformations
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
DiGeorge syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
velocardiofacial syndrome
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
22q11.2 deletion syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

TBX1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.97).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.439 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX1	NM_080646.2 link	c.1009+4367G>A		intron_variant	Intron 8 of 8		NP_542377.1	O43435-1
TBX1	NM_005992.1 link	c.1009+4367G>A		intron_variant	Intron 8 of 9		NP_005983.1	O43435-2Q152R5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBX1	ENST00000329705.11 link	c.1009+4367G>A		intron_variant	Intron 8 of 8	1		ENSP00000331176.7		O43435-1
TBX1	ENST00000359500.7 link	c.1009+4367G>A		intron_variant	Intron 8 of 9	1		ENSP00000352483.3		O43435-2

Frequencies

GnomAD3 genomes

AF:

0.172

AC:

26227

AN:

152114

Hom.:

3068

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0429

Gnomad AMI

AF:

0.221

Gnomad AMR

AF:

0.263

Gnomad ASJ

AF:

0.310

Gnomad EAS

AF:

0.454

Gnomad SAS

AF:

0.192

Gnomad FIN

AF:

0.138

Gnomad MID

AF:

0.177

Gnomad NFE

AF:

0.205

Gnomad OTH

AF:

0.195

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.172

AC:

26225

AN:

152232

Hom.:

3065

Cov.:

AF XY:

0.174

AC XY:

12933

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.0428

AC:

1780

AN:

41562

American (AMR)

AF:

0.264

AC:

4033

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.310

AC:

1075

AN:

3468

East Asian (EAS)

AF:

0.454

AC:

2349

AN:

5176

South Asian (SAS)

AF:

0.191

AC:

923

AN:

4822

European-Finnish (FIN)

AF:

0.138

AC:

1462

AN:

10610

Middle Eastern (MID)

AF:

0.180

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.205

AC:

13942

AN:

67986

Other (OTH)

AF:

0.193

AC:

407

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1052

2104

3157

4209

5261

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

294

588

882

1176

1470

<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:

0.179

Hom.:

1016

Bravo

AF:

0.176

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.97

CADD

Benign

0.16

(source)

DANN

Benign

0.44

PhyloP100

-2.4

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over