chr22-19759683-C-T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The ENST00000332710.8(TBX1):​c.34+6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,612,234 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

TBX1
ENST00000332710.8 splice_region, intron

Scores

2
Splicing: ADA: 0.00001320
2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -0.310

Publications

0 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.79).
BS2
High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TBX1NM_080647.1 linkc.34+6C>T splice_region_variant, intron_variant Intron 2 of 8 NP_542378.1 O43435-3D9ZGG0
TBX1NM_080646.2 linkc.34+6C>T splice_region_variant, intron_variant Intron 2 of 8 NP_542377.1 O43435-1
TBX1NM_005992.1 linkc.34+6C>T splice_region_variant, intron_variant Intron 2 of 9 NP_005983.1 O43435-2Q152R5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TBX1ENST00000332710.8 linkc.34+6C>T splice_region_variant, intron_variant Intron 2 of 8 1 ENSP00000331791.4 O43435-3
TBX1ENST00000329705.11 linkc.34+6C>T splice_region_variant, intron_variant Intron 2 of 8 1 ENSP00000331176.7 O43435-1
TBX1ENST00000359500.7 linkc.34+6C>T splice_region_variant, intron_variant Intron 2 of 9 1 ENSP00000352483.3 O43435-2

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152256
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000411
AC:
6
AN:
1459978
Hom.:
0
Cov.:
34
AF XY:
0.00000413
AC XY:
3
AN XY:
726254
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33456
American (AMR)
AF:
0.00
AC:
0
AN:
44688
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26124
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39676
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86194
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
51940
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00000540
AC:
6
AN:
1111794
Other (OTH)
AF:
0.00
AC:
0
AN:
60338
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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:
0.00000657
AC:
1
AN:
152256
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74384
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41464
American (AMR)
AF:
0.00
AC:
0
AN:
15294
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5200
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4836
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10630
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68040
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.000447
Hom.:
0

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

DiGeorge syndrome Uncertain:1
Aug 23, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

ClinVar contains an entry for this variant (Variation ID: 1018677). This variant has not been reported in the literature in individuals affected with TBX1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.01%). This sequence change falls in intron 2 of the TBX1 gene. It does not directly change the encoded amino acid sequence of the TBX1 protein. It affects a nucleotide within the consensus splice site. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1
Apr 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

TBX1: PM2, BP4 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.79
CADD
Benign
14
DANN
Benign
0.69
PhyloP100
-0.31
Mutation Taster
=94/6
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000013
dbscSNV1_RF
Benign
0.012
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

Other links and lift over

dbSNP: rs1263773731; hg19: chr22-19747206; API