dbSNP rs2301558: TBX1:p.Leu231Leu (chr22-19764306-C-T) – ACMG Classification: Benign (-21 pts)

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.691C>T(p.Leu231Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.262 in 1,612,690 control chromosomes in the GnomAD database, including 61,245 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.34 ( 10424 hom., cov: 33)

Exomes 𝑓: 0.25 ( 50821 hom. )

Consequence

TBX1
NM_001379200.1 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11O:1

Conservation

PhyloP100: 0.0690

Publications

44 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, STRONG Submitted by: PanelApp Australia, 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=-0.49).

BP6

Variant 22-19764306-C-T is Benign according to our data. Variant chr22-19764306-C-T is described in ClinVar as Benign. ClinVar VariationId is 263383.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.069 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.568 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001379200.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TBX1	NM_001379200.1	MANE Select	c.691C>T	p.Leu231Leu	synonymous	Exon 3 of 7	NP_001366129.1	A0A3B3IS18
TBX1	NM_080647.1		c.664C>T	p.Leu222Leu	synonymous	Exon 5 of 9	NP_542378.1	O43435-3
TBX1	NM_080646.2		c.664C>T	p.Leu222Leu	synonymous	Exon 5 of 9	NP_542377.1	O43435-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TBX1	ENST00000649276.2	MANE Select	c.691C>T	p.Leu231Leu	synonymous	Exon 3 of 7	ENSP00000497003.1	A0A3B3IS18
TBX1	ENST00000332710.8	TSL:1	c.664C>T	p.Leu222Leu	synonymous	Exon 5 of 9	ENSP00000331791.4	O43435-3
TBX1	ENST00000329705.11	TSL:1	c.664C>T	p.Leu222Leu	synonymous	Exon 5 of 9	ENSP00000331176.7	O43435-1

Frequencies

GnomAD3 genomes

AF:

0.337

AC:

51241

AN:

152070

Hom.:

10388

Cov.:

show subpopulations

Gnomad AFR

AF:

0.573

Gnomad AMI

AF:

0.263

Gnomad AMR

AF:

0.301

Gnomad ASJ

AF:

0.244

Gnomad EAS

AF:

0.119

Gnomad SAS

AF:

0.360

Gnomad FIN

AF:

0.230

Gnomad MID

AF:

0.361

Gnomad NFE

AF:

0.239

Gnomad OTH

AF:

0.325

GnomAD2 exomes

AF:

0.274

AC:

68669

AN:

250178

AF XY:

0.274

show subpopulations

Gnomad AFR exome

AF:

0.585

Gnomad AMR exome

AF:

0.275

Gnomad ASJ exome

AF:

0.255

Gnomad EAS exome

AF:

0.117

Gnomad FIN exome

AF:

0.238

Gnomad NFE exome

AF:

0.239

Gnomad OTH exome

AF:

0.282

GnomAD4 exome

AF:

0.254

AC:

370397

AN:

1460502

Hom.:

50821

Cov.:

AF XY:

0.256

AC XY:

186342

AN XY:

726604

show subpopulations

African (AFR)

AF:

0.592

AC:

19816

AN:

33474

American (AMR)

AF:

0.282

AC:

12594

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.246

AC:

6427

AN:

26126

East Asian (EAS)

AF:

0.0987

AC:

3917

AN:

39692

South Asian (SAS)

AF:

0.364

AC:

31395

AN:

86256

European-Finnish (FIN)

AF:

0.235

AC:

12295

AN:

52210

Middle Eastern (MID)

AF:

0.338

AC:

1950

AN:

5766

European-Non Finnish (NFE)

AF:

0.239

AC:

265575

AN:

1111888

Other (OTH)

AF:

0.272

AC:

16428

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

18034

36069

54103

72138

90172

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9238

18476

27714

36952

46190

<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:

0.337

AC:

51334

AN:

152188

Hom.:

10424

Cov.:

AF XY:

0.335

AC XY:

24945

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.574

AC:

23833

AN:

41524

American (AMR)

AF:

0.301

AC:

4599

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.244

AC:

846

AN:

3472

East Asian (EAS)

AF:

0.119

AC:

614

AN:

5164

South Asian (SAS)

AF:

0.360

AC:

1736

AN:

4826

European-Finnish (FIN)

AF:

0.230

AC:

2444

AN:

10606

Middle Eastern (MID)

AF:

0.357

AC:

105

AN:

294

European-Non Finnish (NFE)

AF:

0.239

AC:

16227

AN:

67988

Other (OTH)

AF:

0.326

AC:

690

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1614

3228

4843

6457

8071

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

482

964

1446

1928

2410

<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:

0.269

Hom.:

10373

Bravo

AF:

0.351

Asia WGS

AF:

0.270

AC:

939

AN:

3478

EpiCase

AF:

0.244

EpiControl

AF:

0.251

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

not provided (4)

Cardiovascular phenotype (1)

DiGeorge syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.96

PhyloP100

0.069

Mutation Taster

=98/2

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over