NM_001379200.1:c.170_172delCGC

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP3BP6_Moderate

The NM_001379200.1(TBX1):​c.170_172delCGC​(p.Pro57del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00149 in 782,448 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. P57P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0015 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

TBX1
NM_001379200.1 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.41

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: Likely_benign. The variant received -3 ACMG points.

BP3
Nonframeshift variant in repetitive region in NM_001379200.1
BP6
Variant 22-19760999-CCCG-C is Benign according to our data. Variant chr22-19760999-CCCG-C is described in ClinVar as [Likely_benign]. Clinvar id is 3324840.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TBX1NM_001379200.1 linkc.170_172delCGC p.Pro57del disruptive_inframe_deletion Exon 1 of 7 ENST00000649276.2 NP_001366129.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TBX1ENST00000649276.2 linkc.170_172delCGC p.Pro57del disruptive_inframe_deletion Exon 1 of 7 NM_001379200.1 ENSP00000497003.1 A0A3B3IS18

Frequencies

GnomAD3 genomes
AF:
0.00
AC:
0
AN:
145488
Hom.:
0
Cov.:
31
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.00
AC:
0
AN:
292
AF XY:
0.00
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00149
AC:
1165
AN:
782448
Hom.:
0
AF XY:
0.00150
AC XY:
544
AN XY:
362398
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00177
AC:
26
AN:
14698
American (AMR)
AF:
0.00327
AC:
3
AN:
918
Ashkenazi Jewish (ASJ)
AF:
0.00289
AC:
14
AN:
4848
East Asian (EAS)
AF:
0.00180
AC:
6
AN:
3340
South Asian (SAS)
AF:
0.00185
AC:
30
AN:
16252
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
260
Middle Eastern (MID)
AF:
0.00195
AC:
3
AN:
1540
European-Non Finnish (NFE)
AF:
0.00146
AC:
1047
AN:
715028
Other (OTH)
AF:
0.00141
AC:
36
AN:
25564
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.242
Heterozygous variant carriers
0
185
370
556
741
926
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
54
108
162
216
270
<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
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
145488
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
70692
African (AFR)
AF:
0.00
AC:
0
AN:
40636
American (AMR)
AF:
0.00
AC:
0
AN:
14678
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3380
East Asian (EAS)
AF:
0.00
AC:
0
AN:
4970
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4784
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
8282
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
298
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
65558
Other (OTH)
AF:
0.00
AC:
0
AN:
1998

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Cardiovascular phenotype Benign:1
May 15, 2024
Ambry Genetics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
1.4
Mutation Taster
=78/22
polymorphism

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

Other links and lift over

dbSNP: rs886038791; hg19: chr22-19748522; API