dbSNP rs1555895466: TBX1:p.Lys107Glu (chr22-19761162-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001379200.1(TBX1):c.319A>G(p.Lys107Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000739 in 1,353,432 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.4e-7 ( 0 hom. )

Consequence

TBX1
NM_001379200.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.19

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

TBX1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX1	NM_001379200.1 link	c.319A>G	p.Lys107Glu	missense_variant	Exon 1 of 7	ENST00000649276.2	NP_001366129.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBX1	ENST00000649276.2 link	c.319A>G	p.Lys107Glu	missense_variant	Exon 1 of 7		NM_001379200.1	ENSP00000497003.1		A0A3B3IS18

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.39e-7

AC:

AN:

1353432

Hom.:

Cov.:

AF XY:

0.00000148

AC XY:

AN XY:

673518

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

27476

American (AMR)

AF:

0.00

AC:

AN:

36262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22306

East Asian (EAS)

AF:

0.00

AC:

AN:

29798

South Asian (SAS)

AF:

0.00

AC:

AN:

78328

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3992

European-Non Finnish (NFE)

AF:

9.50e-7

AC:

AN:

1052732

Other (OTH)

AF:

0.00

AC:

AN:

53916

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Uncertain

0.030

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.20

.;T;.;.

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.22

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.53

T;T;T;T

M_CAP

Pathogenic

0.98

MetaRNN

Uncertain

0.49

T;T;T;T

MetaSVM

Uncertain

0.090

MutationAssessor

Benign

0.0

N;N;N;.

PhyloP100

4.2

PrimateAI

Pathogenic

0.97

PROVEAN

Benign

-0.70

N;N;N;.

REVEL

Uncertain

0.41

Sift

Benign

0.047

D;T;T;.

Sift4G

Benign

0.18

T;T;T;.

Polyphen

0.99

.;D;.;.

Vest4

0.27

MutPred

0.34

Loss of MoRF binding (P = 0.0045);Loss of MoRF binding (P = 0.0045);Loss of MoRF binding (P = 0.0045);.;

MVP

0.57

MPC

0.74

ClinPred

0.81

GERP RS

3.3

PromoterAI

-0.053

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.30

gMVP

0.52

Mutation Taster

=80/20

polymorphism

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over