rs72646967

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.1216A>C(p.Asn406His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.218 in 1,441,986 control chromosomes in the GnomAD database, including 37,415 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N406S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.19 ( 3490 hom., cov: 32)

Exomes 𝑓: 0.22 ( 33925 hom. )

Consequence

TBX1
NM_001379200.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 2.14

Publications

30 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=0.002857238).

BP6

Variant 22-19766568-A-C is Benign according to our data. Variant chr22-19766568-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 263351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.468 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX1	NM_001379200.1 link	c.1216A>C	p.Asn406His	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.1216A>C	p.Asn406His	missense_variant	Exon 7 of 7		NM_001379200.1	ENSP00000497003.1		A0A3B3IS18

Frequencies

GnomAD3 genomes

AF:

0.185

AC:

27927

AN:

150614

Hom.:

3492

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0457

Gnomad AMI

AF:

0.221

Gnomad AMR

AF:

0.270

Gnomad ASJ

AF:

0.321

Gnomad EAS

AF:

0.485

Gnomad SAS

AF:

0.238

Gnomad FIN

AF:

0.155

Gnomad MID

AF:

0.196

Gnomad NFE

AF:

0.222

Gnomad OTH

AF:

0.207

GnomAD2 exomes

AF:

0.251

AC:

20007

AN:

79850

AF XY:

0.244

show subpopulations

Gnomad AFR exome

AF:

0.0373

Gnomad AMR exome

AF:

0.326

Gnomad ASJ exome

AF:

0.301

Gnomad EAS exome

AF:

0.483

Gnomad FIN exome

AF:

0.152

Gnomad NFE exome

AF:

0.220

Gnomad OTH exome

AF:

0.226

GnomAD4 exome

AF:

0.221

AC:

285760

AN:

1291264

Hom.:

33925

Cov.:

AF XY:

0.222

AC XY:

141502

AN XY:

636556

show subpopulations

African (AFR)

AF:

0.0354

AC:

939

AN:

26498

American (AMR)

AF:

0.311

AC:

8028

AN:

25854

Ashkenazi Jewish (ASJ)

AF:

0.307

AC:

6759

AN:

22038

East Asian (EAS)

AF:

0.471

AC:

12724

AN:

26988

South Asian (SAS)

AF:

0.226

AC:

15503

AN:

68594

European-Finnish (FIN)

AF:

0.162

AC:

5281

AN:

32616

Middle Eastern (MID)

AF:

0.224

AC:

866

AN:

3870

European-Non Finnish (NFE)

AF:

0.217

AC:

224004

AN:

1031862

Other (OTH)

AF:

0.220

AC:

11656

AN:

52944

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

11749

23498

35246

46995

58744

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.185

AC:

27922

AN:

150722

Hom.:

3490

Cov.:

AF XY:

0.188

AC XY:

13808

AN XY:

73626

show subpopulations

African (AFR)

AF:

0.0456

AC:

1880

AN:

41194

American (AMR)

AF:

0.270

AC:

4103

AN:

15198

Ashkenazi Jewish (ASJ)

AF:

0.321

AC:

1111

AN:

3458

East Asian (EAS)

AF:

0.484

AC:

2425

AN:

5006

South Asian (SAS)

AF:

0.237

AC:

1140

AN:

4804

European-Finnish (FIN)

AF:

0.155

AC:

1596

AN:

10298

Middle Eastern (MID)

AF:

0.201

AC:

AN:

284

European-Non Finnish (NFE)

AF:

0.222

AC:

14982

AN:

67480

Other (OTH)

AF:

0.204

AC:

426

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1125

2250

3375

4500

5625

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.211

Hom.:

640

Bravo

AF:

0.186

TwinsUK

AF:

0.217

AC:

806

ALSPAC

AF:

0.210

AC:

810

ESP6500AA

AF:

0.0304

AC:

ESP6500EA

AF:

0.150

AC:

825

ExAC

AF:

0.143

AC:

12700

Asia WGS

AF:

0.300

AC:

1006

AN:

3342

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Apr 04, 2023

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

Significance:Likely benign

Review Status:criteria provided, single submitter

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

- -

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

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

- -

not provided

Benign:3

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

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.87

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.036

LIST_S2

Benign

0.25

T;T

MetaRNN

Benign

0.0029

T;T

MetaSVM

Benign

-1.0

PhyloP100

2.1

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

0.91

N;.

REVEL

Benign

0.22

Sift

Benign

1.0

T;.

Sift4G

Benign

1.0

T;.

Vest4

0.072

MPC

0.55

ClinPred

0.0012

GERP RS

2.9

gMVP

0.27

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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rs72646967

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