Genetic Variant TBX1:p.Pro57dup (chr22-19760999-C-CCCG) – 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.170_172dupCGC(p.Pro57dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000717 in 933,994 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000082 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000070 ( 0 hom. )

Consequence

TBX1
NM_001379200.1 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 1.41

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, 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:

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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 22-19760999-C-CCCG is Benign according to our data. Variant chr22-19760999-C-CCCG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 263404.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000825 (12/145488) while in subpopulation SAS AF = 0.000209 (1/4784). AF 95% confidence interval is 0.0000493. There are 0 homozygotes in GnomAd4. There are 9 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 12 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	UniProt
TBX1	NM_001379200.1	MANE Select	c.170_172dupCGC	p.Pro57dup	disruptive_inframe_insertion	Exon 1 of 7	NP_001366129.1	A0A3B3IS18
TBX1	NM_080647.1		c.143_145dupCGC	p.Pro48dup	disruptive_inframe_insertion	Exon 3 of 9	NP_542378.1	O43435-3
TBX1	NM_080646.2		c.143_145dupCGC	p.Pro48dup	disruptive_inframe_insertion	Exon 3 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.170_172dupCGC	p.Pro57dup	disruptive_inframe_insertion	Exon 1 of 7	ENSP00000497003.1	A0A3B3IS18
TBX1	ENST00000332710.8	TSL:1	c.143_145dupCGC	p.Pro48dup	disruptive_inframe_insertion	Exon 3 of 9	ENSP00000331791.4	O43435-3
TBX1	ENST00000329705.11	TSL:1	c.143_145dupCGC	p.Pro48dup	disruptive_inframe_insertion	Exon 3 of 9	ENSP00000331176.7	O43435-1

Frequencies

GnomAD3 genomes

AF:

0.0000825

AC:

AN:

145488

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000246

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000136

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000201

Gnomad SAS

AF:

0.000209

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000107

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000698

AC:

AN:

788506

Hom.:

Cov.:

AF XY:

0.0000630

AC XY:

AN XY:

365226

show subpopulations

African (AFR)

AF:

0.000135

AC:

AN:

14846

American (AMR)

AF:

0.00

AC:

AN:

932

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

4876

East Asian (EAS)

AF:

0.00

AC:

AN:

3358

South Asian (SAS)

AF:

0.000183

AC:

AN:

16374

European-Finnish (FIN)

AF:

0.00

AC:

AN:

262

Middle Eastern (MID)

AF:

0.000644

AC:

AN:

1552

European-Non Finnish (NFE)

AF:

0.0000652

AC:

AN:

720538

Other (OTH)

AF:

0.0000776

AC:

AN:

25768

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

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:

0.0000825

AC:

AN:

145488

Hom.:

Cov.:

AF XY:

0.000127

AC XY:

AN XY:

70692

show subpopulations

African (AFR)

AF:

0.0000246

AC:

AN:

40636

American (AMR)

AF:

0.000136

AC:

AN:

14678

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3380

East Asian (EAS)

AF:

0.000201

AC:

AN:

4970

South Asian (SAS)

AF:

0.000209

AC:

AN:

4784

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8282

Middle Eastern (MID)

AF:

0.00

AC:

AN:

298

European-Non Finnish (NFE)

AF:

0.000107

AC:

AN:

65558

Other (OTH)

AF:

0.00

AC:

AN:

1998

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.529

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:

0.0000453

ClinVar

ClinVar submissions

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

1.4

Mutation Taster

=87/13

polymorphism

(source)

Splicing

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

Publications

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22-19760999-CCCGCCG-CCCGCCGCCG

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