Genetic Variant NM_001379200.1:c.960A>G (chr22-19765926-A-G) – 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.960A>G(p.Ala320Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.218 in 1,527,280 control chromosomes in the GnomAD database, including 39,847 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.19 ( 3524 hom., cov: 33)

Exomes 𝑓: 0.22 ( 36323 hom. )

Consequence

TBX1
NM_001379200.1 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.830

Publications

23 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=-0.76).

BP6

Variant 22-19765926-A-G is Benign according to our data. Variant chr22-19765926-A-G is described in ClinVar as Benign. ClinVar VariationId is 263444.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.83 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.468 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.960A>G	p.Ala320Ala	synonymous	Exon 6 of 7	NP_001366129.1	A0A3B3IS18
TBX1	NM_080647.1		c.933A>G	p.Ala311Ala	synonymous	Exon 8 of 9	NP_542378.1	O43435-3
TBX1	NM_080646.2		c.933A>G	p.Ala311Ala	synonymous	Exon 8 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.960A>G	p.Ala320Ala	synonymous	Exon 6 of 7	ENSP00000497003.1	A0A3B3IS18
TBX1	ENST00000332710.8	TSL:1	c.933A>G	p.Ala311Ala	synonymous	Exon 8 of 9	ENSP00000331791.4	O43435-3
TBX1	ENST00000329705.11	TSL:1	c.933A>G	p.Ala311Ala	synonymous	Exon 8 of 9	ENSP00000331176.7	O43435-1

Frequencies

GnomAD3 genomes

AF:

0.186

AC:

28121

AN:

151480

Hom.:

3527

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:

0.484

Gnomad SAS

AF:

0.239

Gnomad FIN

AF:

0.156

Gnomad MID

AF:

0.196

Gnomad NFE

AF:

0.222

Gnomad OTH

AF:

0.205

GnomAD2 exomes

AF:

0.230

AC:

28609

AN:

124464

AF XY:

0.229

show subpopulations

Gnomad AFR exome

AF:

0.0208

Gnomad AMR exome

AF:

0.300

Gnomad ASJ exome

AF:

0.287

Gnomad EAS exome

AF:

0.425

Gnomad FIN exome

AF:

0.159

Gnomad NFE exome

AF:

0.204

Gnomad OTH exome

AF:

0.207

GnomAD4 exome

AF:

0.221

AC:

304257

AN:

1375688

Hom.:

36323

Cov.:

AF XY:

0.222

AC XY:

150769

AN XY:

678254

show subpopulations

African (AFR)

AF:

0.0340

AC:

1027

AN:

30232

American (AMR)

AF:

0.297

AC:

9930

AN:

33424

Ashkenazi Jewish (ASJ)

AF:

0.304

AC:

7385

AN:

24296

East Asian (EAS)

AF:

0.460

AC:

15276

AN:

33198

South Asian (SAS)

AF:

0.226

AC:

17465

AN:

77324

European-Finnish (FIN)

AF:

0.162

AC:

7244

AN:

44656

Middle Eastern (MID)

AF:

0.214

AC:

1068

AN:

4988

European-Non Finnish (NFE)

AF:

0.217

AC:

232424

AN:

1070654

Other (OTH)

AF:

0.219

AC:

12438

AN:

56916

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

11745

23489

35234

46978

58723

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8228

16456

24684

32912

41140

<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:

28114

AN:

151592

Hom.:

3524

Cov.:

AF XY:

0.188

AC XY:

13919

AN XY:

74074

show subpopulations

African (AFR)

AF:

0.0456

AC:

1886

AN:

41338

American (AMR)

AF:

0.271

AC:

4137

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.321

AC:

1114

AN:

3470

East Asian (EAS)

AF:

0.483

AC:

2460

AN:

5088

South Asian (SAS)

AF:

0.238

AC:

1146

AN:

4814

European-Finnish (FIN)

AF:

0.156

AC:

1637

AN:

10524

Middle Eastern (MID)

AF:

0.194

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.222

AC:

15050

AN:

67774

Other (OTH)

AF:

0.202

AC:

426

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1109

2219

3328

4438

5547

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

314

628

942

1256

1570

<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.:

808

Bravo

AF:

0.187

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

not provided (3)

Cardiovascular phenotype (1)

DiGeorge syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

(source)

DANN

Benign

0.75

PhyloP100

-0.83

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over