rs72646973

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000329705.11(TBX1):c.*11C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00199 in 1,614,062 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0012 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0021 ( 2 hom. )

Consequence

TBX1
ENST00000329705.11 3_prime_UTR

Scores

Clinical Significance

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

Conservation

PhyloP100: -2.11

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 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 22-19779418-C-T is Benign according to our data. Variant chr22-19779418-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 504975.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00121 (184/152230) while in subpopulation NFE AF = 0.00228 (155/68016). AF 95% confidence interval is 0.00199. There are 1 homozygotes in GnomAd4. There are 86 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 184 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX1	NM_080646.2 link	c.*11C>T		3_prime_UTR_variant	Exon 9 of 9		NP_542377.1	O43435-1
TBX1	NM_005992.1 link	c.1010-3495C>T		intron_variant	Intron 8 of 9		NP_005983.1	O43435-2Q152R5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBX1	ENST00000329705.11 link	c.*11C>T		3_prime_UTR_variant	Exon 9 of 9	1		ENSP00000331176.7		O43435-1
TBX1	ENST00000359500.7 link	c.1010-3495C>T		intron_variant	Intron 8 of 9	1		ENSP00000352483.3		O43435-2

Frequencies

GnomAD3 genomes

AF:

0.00121

AC:

184

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00228

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00131

AC:

330

AN:

251156

AF XY:

0.00132

show subpopulations

Gnomad AFR exome

AF:

0.000247

Gnomad AMR exome

AF:

0.000463

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.000272

Gnomad FIN exome

AF:

0.00116

Gnomad NFE exome

AF:

0.00233

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00207

AC:

3025

AN:

1461832

Hom.:

Cov.:

AF XY:

0.00197

AC XY:

1435

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.000568

AC:

AN:

33480

American (AMR)

AF:

0.000470

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.000139

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00112

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.000695

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00252

AC:

2806

AN:

1111988

Other (OTH)

AF:

0.00166

AC:

100

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

151

301

452

602

753

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00121

AC:

184

AN:

152230

Hom.:

Cov.:

AF XY:

0.00116

AC XY:

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.000361

AC:

AN:

41536

American (AMR)

AF:

0.000196

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00228

AC:

155

AN:

68016

Other (OTH)

AF:

0.00237

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00214

Hom.:

Bravo

AF:

0.00127

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 27, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant classified as Uncertain Significance - Favor Benign. The c.*11C>T varian t in TBX1 has been reported in 1 individual with TOF and his presumably unaffect ed mother. The patient also carried variants in other genes associated with cong enital heart defects (Topf 2014). This variant has been identified in 0.2% (133/ 44688) of European chromosomes by the Exome Aggregation Consortium (ExAC, http:/ /exac.broadinstitute.org; dbSNP rs72646973). Although it has been seen in the ge neral population, its frequency is not high enough to rule out a pathogenic role . In summary, while the clinical significance of the c.*11C>T variant is uncerta in, its frequency suggest that it is more likely to be benign. -

not provided

Benign:1

Sep 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TBX1: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.77

(source)

DANN

Benign

0.64

PhyloP100

-2.1

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Publications

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rs72646973

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