rs1001921296

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2

The NM_001379200.1(TBX1):​c.1082C>T​(p.Pro361Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000378 in 1,349,320 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000037 ( 0 hom. )

Consequence

TBX1
NM_001379200.1 missense

Scores

2
14

Clinical Significance

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

Conservation

PhyloP100: 1.39
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.16933814).
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0000463 (7/151314) while in subpopulation NFE AF= 0.000103 (7/67734). AF 95% confidence interval is 0.0000478. There are 0 homozygotes in gnomad4. There are 1 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TBX1NM_001379200.1 linkuse as main transcriptc.1082C>T p.Pro361Leu missense_variant 7/7 ENST00000649276.2 NP_001366129.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TBX1ENST00000649276.2 linkuse as main transcriptc.1082C>T p.Pro361Leu missense_variant 7/7 NM_001379200.1 ENSP00000497003.1 A0A3B3IS18
TBX1ENST00000332710.8 linkuse as main transcriptc.1055C>T p.Pro352Leu missense_variant 9/91 ENSP00000331791.4 O43435-3
TBX1ENST00000329705.11 linkuse as main transcriptc.1009+432C>T intron_variant 1 ENSP00000331176.7 O43435-1
TBX1ENST00000359500.7 linkuse as main transcriptc.1009+432C>T intron_variant 1 ENSP00000352483.3 O43435-2

Frequencies

GnomAD3 genomes
AF:
0.0000463
AC:
7
AN:
151314
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:
0.000103
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000997
AC:
4
AN:
40124
Hom.:
0
AF XY:
0.0000423
AC XY:
1
AN XY:
23622
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000291
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000367
AC:
44
AN:
1198006
Hom.:
0
Cov.:
23
AF XY:
0.0000256
AC XY:
15
AN XY:
586930
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000602
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000440
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000463
AC:
7
AN:
151314
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
73888
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000103
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000491

ClinVar

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

Submissions by phenotype

DiGeorge syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 14, 2023This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 352 of the TBX1 protein (p.Pro352Leu). This variant is present in population databases (no rsID available, gnomAD 0.02%). This missense change has been observed in individual(s) with TBX1-related conditions (Invitae). This missense change has been observed in at least one individual who was not affected with TBX1-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 573382). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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
Uncertain significance, criteria provided, single submitterclinical testingGeneDxAug 28, 2019In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31428446) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.34
T
BayesDel_noAF
Benign
-0.43
CADD
Benign
19
DANN
Benign
0.94
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.40
N
LIST_S2
Benign
0.38
T;T
M_CAP
Pathogenic
0.98
D
MetaRNN
Benign
0.17
T;T
MetaSVM
Benign
-0.76
T
PrimateAI
Pathogenic
0.89
D
PROVEAN
Benign
-1.3
N;.
REVEL
Benign
0.11
Sift
Benign
0.063
T;.
Sift4G
Benign
0.10
T;.
Vest4
0.16
MutPred
0.31
Gain of stability (P = 0.0727);.;
MVP
0.78
MPC
0.57
ClinPred
0.022
T
GERP RS
1.1
gMVP
0.26

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1001921296; hg19: chr22-19753957; API