rs746335599

Variant names:

Your query was ambiguous. Multiple possible variants found:

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 id is 518565.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX1	NM_001379200.1 link	c.1426_1455delGCCGCCGCTGCCGCAGCTGCCGCGGCCGCC	p.Ala476_Ala485del	conservative_inframe_deletion	Exon 7 of 7	ENST00000649276.2	NP_001366129.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TBX1	ENST00000649276.2 link	c.1426_1455delGCCGCCGCTGCCGCAGCTGCCGCGGCCGCC	p.Ala476_Ala485del	conservative_inframe_deletion	Exon 7 of 7		NM_001379200.1	ENSP00000497003.1	A0A3B3IS18
TBX1	ENST00000332710.8 link	c.1399_1428delGCCGCCGCTGCCGCAGCTGCCGCGGCCGCC	p.Ala467_Ala476del	conservative_inframe_deletion	Exon 9 of 9	1		ENSP00000331791.4	O43435-3
TBX1	ENST00000329705.11 link	c.1009+776_1009+805delGCCGCCGCTGCCGCAGCTGCCGCGGCCGCC		intron_variant	Intron 8 of 8	1		ENSP00000331176.7	O43435-1
TBX1	ENST00000359500.7 link	c.1009+776_1009+805delGCCGCCGCTGCCGCAGCTGCCGCGGCCGCC		intron_variant	Intron 8 of 9	1		ENSP00000352483.3	O43435-2

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

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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000302

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

DiGeorge syndrome

Uncertain:1

Oct 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.1399_1428del, results in the deletion of 10 amino acid(s) of the TBX1 protein (p.Ala467_Ala476del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs746335599, gnomAD 0.05%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with TBX1-related conditions. ClinVar contains an entry for this variant (Variation ID: 518565). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype

Benign:1

Jan 04, 2021

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

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

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rs746335599

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over