chr22-19779259-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000329705.11(TBX1):c.1049C>T(p.Thr350Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 1,613,954 control chromosomes in the GnomAD database, including 32,797 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.18 ( 2689 hom., cov: 33)

Exomes 𝑓: 0.20 ( 30108 hom. )

Consequence

TBX1
ENST00000329705.11 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.779

Publications

38 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0040336847).

BP6

Variant 22-19779259-C-T is Benign according to our data. Variant chr22-19779259-C-T is described in ClinVar as Benign. ClinVar VariationId is 403525.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.344 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000329705.11. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX1	NM_080646.2		c.1049C>T	p.Thr350Met	missense	Exon 9 of 9	NP_542377.1
	TBX1	NM_005992.1		c.1010-3654C>T		intron	N/A	NP_005983.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX1	ENST00000329705.11	TSL:1	c.1049C>T	p.Thr350Met	missense	Exon 9 of 9	ENSP00000331176.7
	TBX1	ENST00000359500.7	TSL:1	c.1010-3654C>T		intron	N/A	ENSP00000352483.3

Frequencies

GnomAD3 genomes

AF:

0.183

AC:

27860

AN:

152138

Hom.:

2682

Cov.:

show subpopulations

Gnomad AFR

AF:

0.143

Gnomad AMI

AF:

0.242

Gnomad AMR

AF:

0.228

Gnomad ASJ

AF:

0.197

Gnomad EAS

AF:

0.119

Gnomad SAS

AF:

0.359

Gnomad FIN

AF:

0.206

Gnomad MID

AF:

0.278

Gnomad NFE

AF:

0.183

Gnomad OTH

AF:

0.205

GnomAD2 exomes

AF:

0.212

AC:

53205

AN:

251322

AF XY:

0.221

show subpopulations

Gnomad AFR exome

AF:

0.146

Gnomad AMR exome

AF:

0.232

Gnomad ASJ exome

AF:

0.212

Gnomad EAS exome

AF:

0.114

Gnomad FIN exome

AF:

0.208

Gnomad NFE exome

AF:

0.190

Gnomad OTH exome

AF:

0.228

GnomAD4 exome

AF:

0.196

AC:

286251

AN:

1461700

Hom.:

30108

Cov.:

AF XY:

0.202

AC XY:

146791

AN XY:

727158

show subpopulations

African (AFR)

AF:

0.145

AC:

4855

AN:

33480

American (AMR)

AF:

0.235

AC:

10491

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.205

AC:

5352

AN:

26136

East Asian (EAS)

AF:

0.0981

AC:

3892

AN:

39694

South Asian (SAS)

AF:

0.361

AC:

31101

AN:

86248

European-Finnish (FIN)

AF:

0.205

AC:

10969

AN:

53398

Middle Eastern (MID)

AF:

0.288

AC:

1659

AN:

5768

European-Non Finnish (NFE)

AF:

0.185

AC:

205740

AN:

1111870

Other (OTH)

AF:

0.202

AC:

12192

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

13358

26717

40075

53434

66792

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7328

14656

21984

29312

36640

<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:

0.183

AC:

27894

AN:

152254

Hom.:

2689

Cov.:

AF XY:

0.187

AC XY:

13955

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.144

AC:

5979

AN:

41542

American (AMR)

AF:

0.228

AC:

3485

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.197

AC:

684

AN:

3470

East Asian (EAS)

AF:

0.119

AC:

620

AN:

5190

South Asian (SAS)

AF:

0.358

AC:

1729

AN:

4830

European-Finnish (FIN)

AF:

0.206

AC:

2187

AN:

10598

Middle Eastern (MID)

AF:

0.276

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.183

AC:

12475

AN:

68006

Other (OTH)

AF:

0.205

AC:

433

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1200

2399

3599

4798

5998

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

308

616

924

1232

1540

<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:

0.187

Hom.:

13890

Bravo

AF:

0.182

TwinsUK

AF:

0.191

AC:

709

ALSPAC

AF:

0.185

AC:

713

ESP6500AA

AF:

0.151

AC:

666

ESP6500EA

AF:

0.183

AC:

1577

ExAC

AF:

0.211

AC:

25627

Asia WGS

AF:

0.233

AC:

809

AN:

3478

EpiCase

AF:

0.197

EpiControl

AF:

0.199

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Jul 14, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.56

CADD

Benign

8.8

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

Eigen

Benign

-0.75

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.00048

LIST_S2

Benign

0.40

MetaRNN

Benign

0.0040

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

PhyloP100

-0.78

PROVEAN

Benign

-1.2

REVEL

Benign

0.27

Sift

Benign

0.048

Sift4G

Uncertain

0.017

Polyphen

1.0

Vest4

0.027

ClinPred

0.040

GERP RS

-3.4

Varity_R

0.016

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over