rs4819522

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_080646.2(TBX1):c.1049C>T(p.Thr350Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 1,613,954 control chromosomes in the GnomAD database, including 32,797 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.18 ( 2689 hom., cov: 33)

Exomes 𝑓: 0.20 ( 30108 hom. )

Consequence

TBX1
NM_080646.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.779

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 (MetaRNN=0.0040336847).

BP6

Variant 22-19779259-C-T is Benign according to our data. Variant chr22-19779259-C-T is described in ClinVar as [Benign]. Clinvar id is 403525.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-19779259-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.344 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX1	NM_080646.2 link	c.1049C>T	p.Thr350Met	missense_variant	Exon 9 of 9		NP_542377.1	O43435-1
TBX1	NM_005992.1 link	c.1010-3654C>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.1049C>T	p.Thr350Met	missense_variant	Exon 9 of 9	1		ENSP00000331176.7		O43435-1
TBX1	ENST00000359500.7 link	c.1010-3654C>T		intron_variant	Intron 8 of 9	1		ENSP00000352483.3		O43435-2

Frequencies

GnomAD3 genomes

AF:

0.183

AC:

27860

AN:

152138

Hom.:

2682

Cov.:

show subpopulations

Gnomad AFR

AF:

0.143

Gnomad AMI

AF:

0.242

Gnomad AMR

AF:

0.228

Gnomad ASJ

AF:

0.197

Gnomad EAS

AF:

0.119

Gnomad SAS

AF:

0.359

Gnomad FIN

AF:

0.206

Gnomad MID

AF:

0.278

Gnomad NFE

AF:

0.183

Gnomad OTH

AF:

0.205

GnomAD3 exomes

AF:

0.212

AC:

53205

AN:

251322

Hom.:

6278

AF XY:

0.221

AC XY:

30004

AN XY:

135852

show subpopulations

Gnomad AFR exome

AF:

0.146

Gnomad AMR exome

AF:

0.232

Gnomad ASJ exome

AF:

0.212

Gnomad EAS exome

AF:

0.114

Gnomad SAS exome

AF:

0.362

Gnomad FIN exome

AF:

0.208

Gnomad NFE exome

AF:

0.190

Gnomad OTH exome

AF:

0.228

GnomAD4 exome

AF:

0.196

AC:

286251

AN:

1461700

Hom.:

30108

Cov.:

AF XY:

0.202

AC XY:

146791

AN XY:

727158

show subpopulations

Gnomad4 AFR exome

AF:

0.145

Gnomad4 AMR exome

AF:

0.235

Gnomad4 ASJ exome

AF:

0.205

Gnomad4 EAS exome

AF:

0.0981

Gnomad4 SAS exome

AF:

0.361

Gnomad4 FIN exome

AF:

0.205

Gnomad4 NFE exome

AF:

0.185

Gnomad4 OTH exome

AF:

0.202

GnomAD4 genome

AF:

0.183

AC:

27894

AN:

152254

Hom.:

2689

Cov.:

AF XY:

0.187

AC XY:

13955

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.144

Gnomad4 AMR

AF:

0.228

Gnomad4 ASJ

AF:

0.197

Gnomad4 EAS

AF:

0.119

Gnomad4 SAS

AF:

0.358

Gnomad4 FIN

AF:

0.206

Gnomad4 NFE

AF:

0.183

Gnomad4 OTH

AF:

0.205

Alfa

AF:

0.192

Hom.:

7727

Bravo

AF:

0.182

TwinsUK

AF:

0.191

AC:

709

ALSPAC

AF:

0.185

AC:

713

ESP6500AA

AF:

0.151

AC:

666

ESP6500EA

AF:

0.183

AC:

1577

ExAC

AF:

0.211

AC:

25627

Asia WGS

AF:

0.233

AC:

809

AN:

3478

EpiCase

AF:

0.197

EpiControl

AF:

0.199

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 14, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.56

CADD

Benign

8.8

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

Eigen

Benign

-0.75

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.00048

LIST_S2

Benign

0.40

MetaRNN

Benign

0.0040

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

PROVEAN

Benign

-1.2

REVEL

Benign

0.27

Sift

Benign

0.048

Sift4G

Uncertain

0.017

Polyphen

1.0

Vest4

0.027

ClinPred

0.040

GERP RS

-3.4

Varity_R

0.016

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