rs565927787

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001379200.1(TBX1):c.1159G>A(p.Gly387Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000227 in 1,309,378 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G387D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0010 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00012 ( 1 hom. )

Consequence

TBX1
NM_001379200.1 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.78

Publications

6 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011241227).

BP6

Variant 22-19766511-G-A is Benign according to our data. Variant chr22-19766511-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 518829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00104 (158/151302) while in subpopulation AFR AF = 0.00365 (151/41414). AF 95% confidence interval is 0.00317. There are 2 homozygotes in GnomAd4. There are 72 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 158 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX1	NM_001379200.1 link	c.1159G>A	p.Gly387Ser	missense_variant	Exon 7 of 7	ENST00000649276.2	NP_001366129.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBX1	ENST00000649276.2 link	c.1159G>A	p.Gly387Ser	missense_variant	Exon 7 of 7		NM_001379200.1	ENSP00000497003.1		A0A3B3IS18

Frequencies

GnomAD3 genomes

AF:

0.00105

AC:

158

AN:

151194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00366

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000198

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000389

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000962

GnomAD2 exomes

AF:

0.000146

AC:

AN:

6856

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0106

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000120

AC:

139

AN:

1158076

Hom.:

Cov.:

AF XY:

0.000116

AC XY:

AN XY:

562308

show subpopulations

African (AFR)

AF:

0.00525

AC:

120

AN:

22866

American (AMR)

AF:

0.000217

AC:

AN:

9210

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15524

East Asian (EAS)

AF:

0.000233

AC:

AN:

25724

South Asian (SAS)

AF:

0.00

AC:

AN:

41782

European-Finnish (FIN)

AF:

0.00

AC:

AN:

26702

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3178

European-Non Finnish (NFE)

AF:

0.00000207

AC:

AN:

966242

Other (OTH)

AF:

0.000192

AC:

AN:

46848

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00104

AC:

158

AN:

151302

Hom.:

Cov.:

AF XY:

0.000974

AC XY:

AN XY:

73942

show subpopulations

African (AFR)

AF:

0.00365

AC:

151

AN:

41414

American (AMR)

AF:

0.000197

AC:

AN:

15204

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.000390

AC:

AN:

5122

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10308

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67664

Other (OTH)

AF:

0.000952

AC:

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000712

Hom.:

Bravo

AF:

0.00112

ExAC

AF:

0.000189

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Apr 29, 2024

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: TBX1 c.1132G>A (p.Gly378Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00023 in 1309378 control chromosomes, predominantly at a frequency of 0.0042 within the African or African-American subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database strongly suggests that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.1132G>A has been reported in the literature in an individuals affected with midline facial defects with hypertelorism without strong evidence of causality (Simioni_2010). This report does not provide unequivocal conclusions about association of the variant with TBX1-Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 20453311). ClinVar contains an entry for this variant (Variation ID: 518829). Based on the evidence outlined above, the variant was classified as likely benign. -

DiGeorge syndrome

Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

TBX1-related disorder

Benign:1

Apr 28, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Jul 21, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 20453311) -

Cardiovascular phenotype

Benign:1

May 21, 2021

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Benign

0.96

Eigen

Benign

-0.96

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.55

T;T

M_CAP

Pathogenic

0.89

MetaRNN

Benign

0.011

T;T

MetaSVM

Benign

-0.60

PhyloP100

1.8

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-0.20

N;.

REVEL

Uncertain

0.30

Sift

Benign

0.037

D;.

Sift4G

Benign

0.44

T;.

Vest4

0.14

MutPred

0.24

Gain of glycosylation at G378 (P = 0.0157);.;

MVP

0.52

MPC

1.1

ClinPred

0.044

GERP RS

-1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

3.2

gMVP

0.27

Mutation Taster

=89/11

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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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