22-19766765-CGCCGCGGCCGCCGCCGCCGCTGCCGCAGCT-C

Position:

chr22-19766765-CGCCGCGGCCGCCGCCGCCGCTGCCGCAGCT-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP3BP6BS1BS2

The NM_001379200.1(TBX1):c.1426_1455del(p.Ala476_Ala485del) variant causes a 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A472A) 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 inframe_deletion

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 1.63

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 submissions are: {Uncertain_significance=1, Likely_benign=1}.

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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX1	NM_001379200.1 linkuse as main transcript	c.1426_1455del	p.Ala476_Ala485del	inframe_deletion	7/7	ENST00000649276.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX1	ENST00000649276.2 linkuse as main transcript	c.1426_1455del	p.Ala476_Ala485del	inframe_deletion	7/7		NM_001379200.1	A2
TBX1	ENST00000332710.8 linkuse as main transcript	c.1399_1428del	p.Ala467_Ala476del	inframe_deletion	9/9	1		P2	O43435-3
TBX1	ENST00000329705.11 linkuse as main transcript	c.1009+776_1009+805del		intron_variant		1		A2	O43435-1
TBX1	ENST00000359500.7 linkuse as main transcript	c.1009+776_1009+805del		intron_variant		1		A2	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

GnomAD3 exomes

AF:

0.000302

AC:

AN:

82690

Hom.:

AF XY:

0.000375

AC XY:

AN XY:

48000

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 SAS exome

AF:

0.000517

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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000455

Gnomad4 ASJ exome

AF:

0.0000463

Gnomad4 EAS exome

AF:

0.0000324

Gnomad4 SAS exome

AF:

0.000441

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000502

Gnomad4 OTH exome

AF:

0.0000735

GnomAD4 genome

AF:

0.0000727

AC:

AN:

151264

Hom.:

Cov.:

AF XY:

0.0000948

AC XY:

AN XY:

73844

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000886

Gnomad4 OTH

AF:

0.00

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 06, 2024

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

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 04, 2021

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

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over