rs781731042

Positions:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS1BS2

The NM_001379200.1(TBX1):c.1076G>A(p.Gly359Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000815 in 1,344,702 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00055 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00085 ( 0 hom. )

Consequence

TBX1
NM_001379200.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: 0.907

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 -8 ACMG points.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000555 (84/151368) while in subpopulation NFE AF= 0.00108 (73/67706). AF 95% confidence interval is 0.000879. There are 0 homozygotes in gnomad4. There are 39 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 84 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBX1	NM_001379200.1 linkuse as main transcript	c.1076G>A	p.Gly359Asp	missense_variant	7/7	ENST00000649276.2	NP_001366129.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBX1	ENST00000649276.2 linkuse as main transcript	c.1076G>A	p.Gly359Asp	missense_variant	7/7		NM_001379200.1	ENSP00000497003	A2
TBX1	ENST00000332710.8 linkuse as main transcript	c.1049G>A	p.Gly350Asp	missense_variant	9/9	1		ENSP00000331791	P2	O43435-3
TBX1	ENST00000329705.11 linkuse as main transcript	c.1009+426G>A		intron_variant		1		ENSP00000331176	A2	O43435-1
TBX1	ENST00000359500.7 linkuse as main transcript	c.1009+426G>A		intron_variant		1		ENSP00000352483	A2	O43435-2

Frequencies

GnomAD3 genomes

AF:

0.000555

AC:

AN:

151260

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000726

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000659

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000582

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000292

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00108

Gnomad OTH

AF:

0.000482

GnomAD3 exomes

AF:

0.000203

AC:

AN:

39464

Hom.:

AF XY:

0.000128

AC XY:

AN XY:

23436

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000137

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000443

Gnomad OTH exome

AF:

0.000797

GnomAD4 exome

AF:

0.000848

AC:

1012

AN:

1193334

Hom.:

Cov.:

AF XY:

0.000821

AC XY:

479

AN XY:

583790

show subpopulations

Gnomad4 AFR exome

AF:

0.0000832

Gnomad4 AMR exome

AF:

0.000122

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000389

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000524

Gnomad4 NFE exome

AF:

0.000980

Gnomad4 OTH exome

AF:

0.000751

GnomAD4 genome

AF:

0.000555

AC:

AN:

151368

Hom.:

Cov.:

AF XY:

0.000527

AC XY:

AN XY:

73986

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.0000658

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000584

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000292

Gnomad4 NFE

AF:

0.00108

Gnomad4 OTH

AF:

0.000477

Alfa

AF:

0.0000530

Hom.:

Bravo

AF:

0.000506

ExAC

AF:

0.000258

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 15, 2024	See Variant Classification Assertion Criteria. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 29, 2018

The p.G350D variant (also known as c.1049G>A), located in coding exon 8 of the TBX1 gene, results from a G to A substitution at nucleotide position 1049. The glycine at codon 350 is replaced by aspartic acid, an amino acid with similar properties. This alteration has been reported in an individual with an aortic arch anomaly; however, clinical details were limited (Gong W et al. J. Med. Genet. 2001 Dec;38:E45). This amino acid position is not well conserved on limited sequence alignment. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

DiGeorge syndrome;C0039685:Tetralogy of Fallot;C0220704:Velocardiofacial syndrome;C1857586:Conotruncal heart malformations

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 30, 2023

Variant summary: TBX1 c.1049G>A (p.Gly350Asp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00082 (1096 variant alleles) in 1345326 control chromosomes in the gnomAD v4 database. c.1049G>A has been reported in the literature in individuals affected with aortic arch anomalies or congenital heart defects (Gong_2001, Zodanu_2021). These reports do not provide unequivocal conclusions about association of the variant with TBX1-Related Disorders. Although reported in the literature in individuals affected with aortic arch anomalies or congenital heart defects (Gong_2001, Zodanu_2021), to our knowledge no penetrant association of this variant with TBX1-related disorders and no experimental evidence has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29500247, 11748311, 29250159, 33995479). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as uncertain significance (n=3) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign. -

DiGeorge syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.090

CADD

Benign

DANN

Benign

0.96

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.62

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.50

T;T

M_CAP

Pathogenic

0.98

MetaRNN

Uncertain

0.49

T;T

MetaSVM

Benign

-0.67

MutationTaster

Benign

1.0

D;D;N

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-0.50

N;.

REVEL

Uncertain

0.52

Sift

Benign

0.24

T;.

Sift4G

Benign

0.41

T;.

Vest4

0.19

MutPred

0.72

Loss of catalytic residue at A349 (P = 0.0672);.;

MVP

0.99

MPC

1.1

ClinPred

0.034

GERP RS

2.2

gMVP

0.32

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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