chr22-19763250-T-C

Variant names:

Variant summary

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

The NM_001379200.1(TBX1):c.447T>C(p.Phe149Phe) variant causes a synonymous change. The variant allele was found at a frequency of 0.221 in 1,613,388 control chromosomes in the GnomAD database, including 43,398 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.19 ( 3508 hom., cov: 33)

Exomes 𝑓: 0.22 ( 39890 hom. )

Consequence

TBX1
NM_001379200.1 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 3.74

Publications

29 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 (BayesDel_noAF=-0.67).

BP6

Variant 22-19763250-T-C is Benign according to our data. Variant chr22-19763250-T-C is described in ClinVar as Benign. ClinVar VariationId is 263350.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.459 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX1	NM_001379200.1 link	c.447T>C	p.Phe149Phe	synonymous_variant	Exon 2 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.447T>C	p.Phe149Phe	synonymous_variant	Exon 2 of 7		NM_001379200.1	ENSP00000497003.1		A0A3B3IS18

Frequencies

GnomAD3 genomes

AF:

0.185

AC:

28166

AN:

152076

Hom.:

3510

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0455

Gnomad AMI

AF:

0.221

Gnomad AMR

AF:

0.271

Gnomad ASJ

AF:

0.320

Gnomad EAS

AF:

0.475

Gnomad SAS

AF:

0.237

Gnomad FIN

AF:

0.155

Gnomad MID

AF:

0.196

Gnomad NFE

AF:

0.222

Gnomad OTH

AF:

0.206

GnomAD2 exomes

AF:

0.243

AC:

60939

AN:

251132

AF XY:

0.242

show subpopulations

Gnomad AFR exome

AF:

0.0409

Gnomad AMR exome

AF:

0.330

Gnomad ASJ exome

AF:

0.303

Gnomad EAS exome

AF:

0.471

Gnomad FIN exome

AF:

0.160

Gnomad NFE exome

AF:

0.224

Gnomad OTH exome

AF:

0.224

GnomAD4 exome

AF:

0.225

AC:

328268

AN:

1461192

Hom.:

39890

Cov.:

AF XY:

0.226

AC XY:

163969

AN XY:

726928

show subpopulations

African (AFR)

AF:

0.0376

AC:

1259

AN:

33472

American (AMR)

AF:

0.321

AC:

14347

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.310

AC:

8108

AN:

26122

East Asian (EAS)

AF:

0.469

AC:

18626

AN:

39696

South Asian (SAS)

AF:

0.230

AC:

19845

AN:

86240

European-Finnish (FIN)

AF:

0.163

AC:

8720

AN:

53380

Middle Eastern (MID)

AF:

0.219

AC:

1264

AN:

5768

European-Non Finnish (NFE)

AF:

0.218

AC:

242801

AN:

1111446

Other (OTH)

AF:

0.220

AC:

13298

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

13290

26579

39869

53158

66448

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8464

16928

25392

33856

42320

<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:

0.185

AC:

28164

AN:

152196

Hom.:

3508

Cov.:

AF XY:

0.188

AC XY:

13957

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.0454

AC:

1886

AN:

41548

American (AMR)

AF:

0.271

AC:

4151

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.320

AC:

1112

AN:

3470

East Asian (EAS)

AF:

0.474

AC:

2439

AN:

5142

South Asian (SAS)

AF:

0.236

AC:

1142

AN:

4830

European-Finnish (FIN)

AF:

0.155

AC:

1646

AN:

10614

Middle Eastern (MID)

AF:

0.201

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.222

AC:

15097

AN:

67972

Other (OTH)

AF:

0.203

AC:

430

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1143

2286

3428

4571

5714

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

316

632

948

1264

1580

<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:

0.213

Hom.:

3854

Bravo

AF:

0.186

Asia WGS

AF:

0.309

AC:

1078

AN:

3478

EpiCase

AF:

0.228

EpiControl

AF:

0.233

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 16, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 04, 2023

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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:3

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 07, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

DiGeorge syndrome

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Jun 12, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as 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

BayesDel_noAF

Benign

-0.67

CADD

Benign

(source)

DANN

Benign

0.89

PhyloP100

3.7

Mutation Taster

=97/3

polymorphism (auto)

(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