rs28649236

Variant names:

• chr22-19759665-A-G
• rs28649236
• ENST00000332710.8:c.22A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000332710.8(TBX1):​c.22A>G​(p.Arg8Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,182 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TBX1 ENST00000332710.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.712
• Publications: 11 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3235361).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX1	NM_080647.1	c.22A>G	p.Arg8Gly	missense_variant	Exon 2 of 9		NP_542378.1
TBX1	NM_080646.2	c.22A>G	p.Arg8Gly	missense_variant	Exon 2 of 9		NP_542377.1
TBX1	NM_005992.1	c.22A>G	p.Arg8Gly	missense_variant	Exon 2 of 10		NP_005983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBX1	ENST00000332710.8	c.22A>G	p.Arg8Gly	missense_variant	Exon 2 of 9	1		ENSP00000331791.4
TBX1	ENST00000329705.11	c.22A>G	p.Arg8Gly	missense_variant	Exon 2 of 9	1		ENSP00000331176.7
TBX1	ENST00000359500.7	c.22A>G	p.Arg8Gly	missense_variant	Exon 2 of 10	1		ENSP00000352483.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000405 AC: 1 AN: 246656 AF XY: 0.00000745

Gnomad AFR exome AF: 0.00

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: 6.85e-7 AC: 1 AN: 1460182 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 726382

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52014

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111860

Other (OTH) AF: 0.00 AC: 0 AN: 60354

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.19
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	.;T;.
Eigen	Benign	0.022
Eigen_PC	Benign	-0.0067
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.81	T;T;T
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.32	T;T;T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	1.0	L;L;L
PhyloP100		0.71
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.98	N;N;N
REVEL	Uncertain	0.48
Sift	Pathogenic	0.0	D;D;D
Sift4G	Benign	0.063	T;T;T
Polyphen		0.99	.;D;.
Vest4		0.44
MutPred		0.27		Gain of catalytic residue at R8 (P = 0.0205);Gain of catalytic residue at R8 (P = 0.0205);Gain of catalytic residue at R8 (P = 0.0205);
MVP		0.99
MPC		2.2
ClinPred		0.56	D
GERP RS		1.1
Varity_R		0.23
gMVP		0.54
Mutation Taster		=25/75	disease causing

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

Other links and lift over

dbSNP: rs28649236; hg19: chr22-19747188;