Genetic Variant TBX1:p.Ala476_Ala485del (chr22-19766765-CGCCGCGGCCGCCGCCGCCGCTGCCGCAGCT-C) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP3BP6BS1BS2

The NM_001379200.1(TBX1):c.1426_1455delGCCGCCGCTGCCGCAGCTGCCGCGGCCGCC(p.Ala476_Ala485del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000694 in 1,469,864 control chromosomes in the GnomAD database, including 2 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A476A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000073 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000069 ( 2 hom. )

Consequence

TBX1
NM_001379200.1 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 1.63

Publications

0 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 -10 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001379200.1

BP6

Variant 22-19766765-CGCCGCGGCCGCCGCCGCCGCTGCCGCAGCT-C is Benign according to our data. Variant chr22-19766765-CGCCGCGGCCGCCGCCGCCGCTGCCGCAGCT-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 518565.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000727 (11/151264) while in subpopulation SAS AF = 0.00104 (5/4820). AF 95% confidence interval is 0.000408. There are 0 homozygotes in GnomAd4. There are 7 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 11 AD gene.

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
TBX1	NM_001379200.1	MANE Select	c.1426_1455delGCCGCCGCTGCCGCAGCTGCCGCGGCCGCC	p.Ala476_Ala485del	conservative_inframe_deletion	Exon 7 of 7	NP_001366129.1
TBX1	NM_080647.1		c.1399_1428delGCCGCCGCTGCCGCAGCTGCCGCGGCCGCC	p.Ala467_Ala476del	conservative_inframe_deletion	Exon 9 of 9	NP_542378.1
TBX1	NM_080646.2		c.1009+776_1009+805delGCCGCCGCTGCCGCAGCTGCCGCGGCCGCC		intron	N/A	NP_542377.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TBX1	ENST00000649276.2	MANE Select	c.1426_1455delGCCGCCGCTGCCGCAGCTGCCGCGGCCGCC	p.Ala476_Ala485del	conservative_inframe_deletion	Exon 7 of 7	ENSP00000497003.1
TBX1	ENST00000332710.8	TSL:1	c.1399_1428delGCCGCCGCTGCCGCAGCTGCCGCGGCCGCC	p.Ala467_Ala476del	conservative_inframe_deletion	Exon 9 of 9	ENSP00000331791.4
TBX1	ENST00000329705.11	TSL:1	c.1009+776_1009+805delGCCGCCGCTGCCGCAGCTGCCGCGGCCGCC		intron	N/A	ENSP00000331176.7

Frequencies

GnomAD3 genomes

AF:

0.0000727

AC:

AN:

151264

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000886

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000302

AC:

AN:

82690

AF XY:

0.000375

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000924

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000439

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000690

AC:

AN:

1318600

Hom.:

AF XY:

0.0000767

AC XY:

AN XY:

651514

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25766

American (AMR)

AF:

0.0000455

AC:

AN:

21956

Ashkenazi Jewish (ASJ)

AF:

0.0000463

AC:

AN:

21586

East Asian (EAS)

AF:

0.0000324

AC:

AN:

30824

South Asian (SAS)

AF:

0.000441

AC:

AN:

70330

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33074

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4468

European-Non Finnish (NFE)

AF:

0.0000502

AC:

AN:

1056152

Other (OTH)

AF:

0.0000735

AC:

AN:

54444

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.594

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000727

AC:

AN:

151264

Hom.:

Cov.:

AF XY:

0.0000948

AC XY:

AN XY:

73844

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41066

American (AMR)

AF:

0.00

AC:

AN:

15232

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3458

East Asian (EAS)

AF:

0.00

AC:

AN:

5134

South Asian (SAS)

AF:

0.00104

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10508

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000886

AC:

AN:

67746

Other (OTH)

AF:

0.00

AC:

AN:

2074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

Bravo

AF:

0.0000302

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cardiovascular phenotype (1)

DiGeorge syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.6

Mutation Taster

=175/25

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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