rs781731042

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_001379200.1(TBX1):c.1076G>A(p.Gly359Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000815 in 1,344,702 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G359V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00055 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00085 ( 0 hom. )

Consequence

TBX1
NM_001379200.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: 0.907

Publications

5 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 -9 ACMG points.

BP6

Variant 22-19766428-G-A is Benign according to our data. Variant chr22-19766428-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 518715.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000555 (84/151368) while in subpopulation NFE AF = 0.00108 (73/67706). AF 95% confidence interval is 0.000879. There are 0 homozygotes in GnomAd4. There are 39 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 84 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX1	NM_001379200.1 link	c.1076G>A	p.Gly359Asp	missense_variant	Exon 7 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.1076G>A	p.Gly359Asp	missense_variant	Exon 7 of 7		NM_001379200.1	ENSP00000497003.1

Frequencies

GnomAD3 genomes

AF:

0.000555

AC:

AN:

151260

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000726

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000659

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000582

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000292

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00108

Gnomad OTH

AF:

0.000482

GnomAD2 exomes

AF:

0.000203

AC:

AN:

39464

AF XY:

0.000128

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000137

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000443

Gnomad OTH exome

AF:

0.000797

GnomAD4 exome

AF:

0.000848

AC:

1012

AN:

1193334

Hom.:

Cov.:

AF XY:

0.000821

AC XY:

479

AN XY:

583790

show subpopulations

African (AFR)

AF:

0.0000832

AC:

AN:

24042

American (AMR)

AF:

0.000122

AC:

AN:

16408

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18324

East Asian (EAS)

AF:

0.0000389

AC:

AN:

25734

South Asian (SAS)

AF:

0.00

AC:

AN:

52962

European-Finnish (FIN)

AF:

0.000524

AC:

AN:

28632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3334

European-Non Finnish (NFE)

AF:

0.000980

AC:

956

AN:

975968

Other (OTH)

AF:

0.000751

AC:

AN:

47930

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

109

163

218

272

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

114

152

190

<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:

0.000555

AC:

AN:

151368

Hom.:

Cov.:

AF XY:

0.000527

AC XY:

AN XY:

73986

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41452

American (AMR)

AF:

0.0000658

AC:

AN:

15206

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.000584

AC:

AN:

5136

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000292

AC:

AN:

10286

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00108

AC:

AN:

67706

Other (OTH)

AF:

0.000477

AC:

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000530

Hom.:

Bravo

AF:

0.000506

ExAC

AF:

0.000258

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:2

Nov 30, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: TBX1 c.1049G>A (p.Gly350Asp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00082 (1096 variant alleles) in 1345326 control chromosomes in the gnomAD v4 database. c.1049G>A has been reported in the literature in individuals affected with aortic arch anomalies or congenital heart defects (Gong_2001, Zodanu_2021). These reports do not provide unequivocal conclusions about association of the variant with TBX1-Related Disorders. Although reported in the literature in individuals affected with aortic arch anomalies or congenital heart defects (Gong_2001, Zodanu_2021), to our knowledge no penetrant association of this variant with TBX1-related disorders and no experimental evidence has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29500247, 11748311, 29250159, 33995479). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as uncertain significance (n=3) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign. -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Jun 15, 2024

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TBX1: BS1, BS2 -

Cardiovascular phenotype

Uncertain:1

Aug 29, 2018

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.G350D variant (also known as c.1049G>A), located in coding exon 8 of the TBX1 gene, results from a G to A substitution at nucleotide position 1049. The glycine at codon 350 is replaced by aspartic acid, an amino acid with similar properties. This alteration has been reported in an individual with an aortic arch anomaly; however, clinical details were limited (Gong W et al. J. Med. Genet. 2001 Dec;38:E45). This amino acid position is not well conserved on limited sequence alignment. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

DiGeorge syndrome;C0039685:Tetralogy of Fallot;C0220704:Velocardiofacial syndrome;C1857586:Conotruncal heart malformations

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

DiGeorge syndrome

Benign:1

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.090

CADD

Benign

(source)

DANN

Benign

0.96

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.62

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.50

T;T

M_CAP

Pathogenic

0.98

MetaRNN

Uncertain

0.49

T;T

MetaSVM

Benign

-0.67

PhyloP100

0.91

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-0.50

N;.

REVEL

Uncertain

0.52

Sift

Benign

0.24

T;.

Sift4G

Benign

0.41

T;.

Vest4

0.19

MutPred

0.72

Loss of catalytic residue at A349 (P = 0.0672);.;

MVP

0.99

MPC

1.1

ClinPred

0.034

GERP RS

2.2

gMVP

0.32

Mutation Taster

=31/69

disease causing

(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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over