Genetic Variant TBX1:p.Gly415Asp (chr22-19766596-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.1244G>A(p.Gly415Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000363 in 1,488,368 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G415G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000037 ( 0 hom. )

Consequence

TBX1
NM_001379200.1 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.868

Publications

2 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=0.0067380667).

BP6

Variant 22-19766596-G-A is Benign according to our data. Variant chr22-19766596-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 455789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000264 (4/151284) while in subpopulation AMR AF = 0.000263 (4/15206). AF 95% confidence interval is 0.0000891. There are 0 homozygotes in GnomAd4. There are 2 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAdExome4 at 50 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.1244G>A	p.Gly415Asp	missense	Exon 7 of 7	NP_001366129.1	A0A3B3IS18
TBX1	NM_080647.1		c.1217G>A	p.Gly406Asp	missense	Exon 9 of 9	NP_542378.1	O43435-3
TBX1	NM_080646.2		c.1009+594G>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.1244G>A	p.Gly415Asp	missense	Exon 7 of 7	ENSP00000497003.1	A0A3B3IS18
TBX1	ENST00000332710.8	TSL:1	c.1217G>A	p.Gly406Asp	missense	Exon 9 of 9	ENSP00000331791.4	O43435-3
TBX1	ENST00000329705.11	TSL:1	c.1009+594G>A		intron	N/A	ENSP00000331176.7	O43435-1

Frequencies

GnomAD3 genomes

AF:

0.0000264

AC:

AN:

151284

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000263

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000327

AC:

AN:

116340

AF XY:

0.000239

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00181

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:

0.0000374

AC:

AN:

1337084

Hom.:

Cov.:

AF XY:

0.0000332

AC XY:

AN XY:

662266

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27656

American (AMR)

AF:

0.00151

AC:

AN:

31754

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23086

East Asian (EAS)

AF:

0.00

AC:

AN:

29028

South Asian (SAS)

AF:

0.00

AC:

AN:

74436

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34520

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4322

European-Non Finnish (NFE)

AF:

9.46e-7

AC:

AN:

1057308

Other (OTH)

AF:

0.0000182

AC:

AN:

54974

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.529

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:

0.0000264

AC:

AN:

151284

Hom.:

Cov.:

AF XY:

0.0000271

AC XY:

AN XY:

73838

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41302

American (AMR)

AF:

0.000263

AC:

AN:

15206

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5106

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10354

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67728

Other (OTH)

AF:

0.00

AC:

AN:

2076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.563

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:

0.00

Hom.:

Bravo

AF:

0.000125

ExAC

AF:

0.000180

AC:

ClinVar

ClinVar submissions as Germline

Significance:Benign/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

0.23

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Uncertain

0.98

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.54

MetaRNN

Benign

0.0067

MetaSVM

Benign

-0.78

PhyloP100

0.87

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-0.69

REVEL

Benign

0.17

Sift

Benign

0.065

Sift4G

Benign

0.63

Vest4

0.25

MutPred

0.30

Gain of solvent accessibility (P = 0.0638)

MVP

0.64

MPC

0.85

ClinPred

0.018

GERP RS

1.8

gMVP

0.26

Mutation Taster

=96/4

polymorphism

(source)

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

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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