dbSNP rs565927787: TBX1:p.Gly387Ser (chr22-19766511-G-A) – ACMG Classification: Benign (-20 pts)

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, STRONG Submitted by: PanelApp Australia, 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001379200.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TBX1	NM_001379200.1	MANE Select	c.1159G>A	p.Gly387Ser	missense	Exon 7 of 7	NP_001366129.1	A0A3B3IS18
TBX1	NM_080647.1		c.1132G>A	p.Gly378Ser	missense	Exon 9 of 9	NP_542378.1	O43435-3
TBX1	NM_080646.2		c.1009+509G>A		intron	N/A	NP_542377.1	O43435-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TBX1	ENST00000649276.2	MANE Select	c.1159G>A	p.Gly387Ser	missense	Exon 7 of 7	ENSP00000497003.1	A0A3B3IS18
TBX1	ENST00000332710.8	TSL:1	c.1132G>A	p.Gly378Ser	missense	Exon 9 of 9	ENSP00000331791.4	O43435-3
TBX1	ENST00000329705.11	TSL:1	c.1009+509G>A		intron	N/A	ENSP00000331176.7	O43435-1

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

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cardiovascular phenotype (1)

DiGeorge syndrome (1)

not provided (1)

not specified (1)

TBX1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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

M_CAP

Pathogenic

0.89

MetaRNN

Benign

0.011

MetaSVM

Benign

-0.60

PhyloP100

1.8

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-0.20

REVEL

Uncertain

0.30

Sift

Benign

0.037

Sift4G

Benign

0.44

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over