chr22-19766438-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001379200.1(TBX1):c.1086A>G(p.Ala362Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0686 in 1,343,886 control chromosomes in the GnomAD database, including 3,899 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.093 ( 926 hom., cov: 33)

Exomes 𝑓: 0.065 ( 2973 hom. )

Consequence

TBX1
NM_001379200.1 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -1.53

Publications

8 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 22-19766438-A-G is Benign according to our data. Variant chr22-19766438-A-G is described in ClinVar as Benign. ClinVar VariationId is 263355.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.53 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.183 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX1	NM_001379200.1 link	c.1086A>G	p.Ala362Ala	synonymous_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.1086A>G	p.Ala362Ala	synonymous_variant	Exon 7 of 7		NM_001379200.1	ENSP00000497003.1		A0A3B3IS18

Frequencies

GnomAD3 genomes

AF:

0.0933

AC:

14080

AN:

150968

Hom.:

925

Cov.:

show subpopulations

Gnomad AFR

AF:

0.187

Gnomad AMI

AF:

0.110

Gnomad AMR

AF:

0.0622

Gnomad ASJ

AF:

0.0570

Gnomad EAS

AF:

0.000586

Gnomad SAS

AF:

0.0156

Gnomad FIN

AF:

0.0311

Gnomad MID

AF:

0.0784

Gnomad NFE

AF:

0.0673

Gnomad OTH

AF:

0.0829

GnomAD2 exomes

AF:

0.0480

AC:

1827

AN:

38034

AF XY:

0.0449

show subpopulations

Gnomad AFR exome

AF:

0.190

Gnomad AMR exome

AF:

0.0399

Gnomad ASJ exome

AF:

0.0594

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0291

Gnomad NFE exome

AF:

0.0655

Gnomad OTH exome

AF:

0.0593

GnomAD4 exome

AF:

0.0655

AC:

78102

AN:

1192808

Hom.:

2973

Cov.:

AF XY:

0.0638

AC XY:

37286

AN XY:

584386

show subpopulations

African (AFR)

AF:

0.196

AC:

4687

AN:

23944

American (AMR)

AF:

0.0496

AC:

784

AN:

15792

Ashkenazi Jewish (ASJ)

AF:

0.0581

AC:

1063

AN:

18304

East Asian (EAS)

AF:

0.000155

AC:

AN:

25778

South Asian (SAS)

AF:

0.0209

AC:

1110

AN:

53150

European-Finnish (FIN)

AF:

0.0353

AC:

1020

AN:

28888

Middle Eastern (MID)

AF:

0.0611

AC:

205

AN:

3354

European-Non Finnish (NFE)

AF:

0.0675

AC:

65879

AN:

975320

Other (OTH)

AF:

0.0694

AC:

3350

AN:

48278

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

3494

6987

10481

13974

17468

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2684

5368

8052

10736

13420

<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:

0.0932

AC:

14085

AN:

151078

Hom.:

926

Cov.:

AF XY:

0.0891

AC XY:

6582

AN XY:

73846

show subpopulations

African (AFR)

AF:

0.187

AC:

7703

AN:

41300

American (AMR)

AF:

0.0621

AC:

944

AN:

15198

Ashkenazi Jewish (ASJ)

AF:

0.0570

AC:

197

AN:

3458

East Asian (EAS)

AF:

0.000588

AC:

AN:

5102

South Asian (SAS)

AF:

0.0154

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0311

AC:

320

AN:

10276

Middle Eastern (MID)

AF:

0.0839

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.0672

AC:

4548

AN:

67632

Other (OTH)

AF:

0.0821

AC:

172

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

613

1225

1838

2450

3063

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

140

280

420

560

700

<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:

0.0838

Hom.:

Bravo

AF:

0.0991

Asia WGS

AF:

0.0190

AC:

AN:

3382

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Apr 10, 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

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

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

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

DiGeorge syndrome

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Jul 15, 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

-0.75

CADD

Benign

1.9

(source)

DANN

Benign

0.24

PhyloP100

-1.5

Mutation Taster

=100/0

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