dbSNP rs369050575: TBX1:p.Lys112del (chr22-19761172-TGAA-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PM4_SupportingBP6BS1BS2

The NM_001379200.1(TBX1):c.336_338delGAA(p.Lys112del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.000142 in 1,526,856 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 1 hom. )

Consequence

TBX1
NM_001379200.1 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 4.20

Publications

1 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 -8 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_001379200.1. Strenght limited to Supporting due to length of the change: 1aa.

BP6

Variant 22-19761172-TGAA-T is Benign according to our data. Variant chr22-19761172-TGAA-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 455791.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000332 (50/150402) while in subpopulation EAS AF = 0.00731 (37/5062). AF 95% confidence interval is 0.00545. There are 0 homozygotes in GnomAd4. There are 24 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 50 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.336_338delGAA	p.Lys112del	disruptive_inframe_deletion	Exon 1 of 7	NP_001366129.1	A0A3B3IS18
TBX1	NM_080647.1		c.309_311delGAA	p.Lys103del	disruptive_inframe_deletion	Exon 3 of 9	NP_542378.1	O43435-3
TBX1	NM_080646.2		c.309_311delGAA	p.Lys103del	disruptive_inframe_deletion	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.336_338delGAA	p.Lys112del	disruptive_inframe_deletion	Exon 1 of 7	ENSP00000497003.1	A0A3B3IS18
TBX1	ENST00000332710.8	TSL:1	c.309_311delGAA	p.Lys103del	disruptive_inframe_deletion	Exon 3 of 9	ENSP00000331791.4	O43435-3
TBX1	ENST00000329705.11	TSL:1	c.309_311delGAA	p.Lys103del	disruptive_inframe_deletion	Exon 3 of 9	ENSP00000331176.7	O43435-1

Frequencies

GnomAD3 genomes

AF:

0.000333

AC:

AN:

150306

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000977

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000264

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00728

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000148

Gnomad OTH

AF:

0.00193

GnomAD2 exomes

AF:

0.000398

AC:

AN:

198560

AF XY:

0.000290

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00655

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.000121

AC:

167

AN:

1376454

Hom.:

AF XY:

0.0000949

AC XY:

AN XY:

684920

show subpopulations

African (AFR)

AF:

0.0000356

AC:

AN:

28122

American (AMR)

AF:

0.00

AC:

AN:

37710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23072

East Asian (EAS)

AF:

0.00312

AC:

AN:

31374

South Asian (SAS)

AF:

0.0000251

AC:

AN:

79748

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50452

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4186

European-Non Finnish (NFE)

AF:

0.00000281

AC:

AN:

1066394

Other (OTH)

AF:

0.00114

AC:

AN:

55396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.000332

AC:

AN:

150402

Hom.:

Cov.:

AF XY:

0.000327

AC XY:

AN XY:

73430

show subpopulations

African (AFR)

AF:

0.0000974

AC:

AN:

41056

American (AMR)

AF:

0.000264

AC:

AN:

15162

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00731

AC:

AN:

5062

South Asian (SAS)

AF:

0.00

AC:

AN:

4772

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9992

Middle Eastern (MID)

AF:

0.00

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.0000148

AC:

AN:

67616

Other (OTH)

AF:

0.00192

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

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:

0.000142

Hom.:

Bravo

AF:

0.000310

Asia WGS

AF:

0.00325

AC:

AN:

3404

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Cardiovascular phenotype (1)

DiGeorge syndrome (1)

not specified (1)

TBX1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.2

Mutation Taster

=54/46

polymorphism

(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