22-19759605-C-T

Position:

chr22-19759605-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_080647.1(TBX1):c.-39C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00156 in 1,609,706 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00091 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0016 ( 8 hom. )

Consequence

TBX1
NM_080647.1 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 2.11

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 22-19759605-C-T is Benign according to our data. Variant chr22-19759605-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 379734.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-19759605-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000906 (138/152374) while in subpopulation SAS AF= 0.00869 (42/4832). AF 95% confidence interval is 0.00661. There are 1 homozygotes in gnomad4. There are 71 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 138 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	#exon/exons	Protein	UniProt
TBX1	NM_080647.1 link	c.-39C>T	5_prime_UTR_premature_start_codon_gain_variant	2/9	NP_542378.1	O43435-3D9ZGG0
TBX1	NM_080646.2 link	c.-39C>T	5_prime_UTR_premature_start_codon_gain_variant	2/9	NP_542377.1	O43435-1
TBX1	NM_005992.1 link	c.-39C>T	5_prime_UTR_premature_start_codon_gain_variant	2/10	NP_005983.1	O43435-2Q152R5

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	Protein	UniProt
TBX1	ENST00000332710 link	c.-39C>T	5_prime_UTR_premature_start_codon_gain_variant	2/9	1	ENSP00000331791.4	O43435-3
TBX1	ENST00000329705 link	c.-39C>T	5_prime_UTR_premature_start_codon_gain_variant	2/9	1	ENSP00000331176.7	O43435-1
TBX1	ENST00000359500 link	c.-39C>T	5_prime_UTR_premature_start_codon_gain_variant	2/10	1	ENSP00000352483.3	O43435-2

Frequencies

GnomAD3 genomes

AF:

0.000906

AC:

138

AN:

152256

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00868

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00123

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00194

AC:

466

AN:

240380

Hom.:

AF XY:

0.00247

AC XY:

324

AN XY:

131240

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000645

Gnomad ASJ exome

AF:

0.000204

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00864

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00164

Gnomad OTH exome

AF:

0.00118

GnomAD4 exome

AF:

0.00163

AC:

2380

AN:

1457332

Hom.:

Cov.:

AF XY:

0.00187

AC XY:

1352

AN XY:

724886

show subpopulations

Gnomad4 AFR exome

AF:

0.000240

Gnomad4 AMR exome

AF:

0.000539

Gnomad4 ASJ exome

AF:

0.000154

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00844

Gnomad4 FIN exome

AF:

0.0000195

Gnomad4 NFE exome

AF:

0.00133

Gnomad4 OTH exome

AF:

0.00209

GnomAD4 genome

AF:

0.000906

AC:

138

AN:

152374

Hom.:

Cov.:

AF XY:

0.000953

AC XY:

AN XY:

74512

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000326

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00869

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00123

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000613

Hom.:

Bravo

AF:

0.000718

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	TBX1: BS2 -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 26, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

DiGeorge syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 08, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

DANN

Benign

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

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