22-19770705-A-G

Variant names:

• chr22-19770705-A-G
• rs2238777
• ENST00000329705.11:c.1009+4703A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000329705.11(TBX1):​c.1009+4703A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.536 in 152,068 control chromosomes in the GnomAD database, including 22,348 homozygotes. 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: 𝑓 0.54 (22348 hom., cov: 32)
• Consequence: TBX1 ENST00000329705.11 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.814
• Publications: 10 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.622 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000329705.11. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX1	NM_080646.2		c.1009+4703A>G		intron	N/A	NP_542377.1
	TBX1	NM_005992.1		c.1009+4703A>G		intron	N/A	NP_005983.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX1	ENST00000329705.11	TSL:1	c.1009+4703A>G		intron	N/A	ENSP00000331176.7
	TBX1	ENST00000359500.7	TSL:1	c.1009+4703A>G		intron	N/A	ENSP00000352483.3

Frequencies

GnomAD3 genomes AF: 0.536 AC: 81378 AN: 151950 Hom.: 22314 Cov.: 32

Gnomad AFR AF: 0.628

Gnomad AMI AF: 0.509

Gnomad AMR AF: 0.590

Gnomad ASJ AF: 0.579

Gnomad EAS AF: 0.596

Gnomad SAS AF: 0.605

Gnomad FIN AF: 0.393

Gnomad MID AF: 0.583

Gnomad NFE AF: 0.477

Gnomad OTH AF: 0.549

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.536 AC: 81470 AN: 152068 Hom.: 22348 Cov.: 32 AF XY: 0.536 AC XY: 39814 AN XY: 74318

African (AFR) AF: 0.629 AC: 26071 AN: 41474

American (AMR) AF: 0.590 AC: 9024 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.579 AC: 2011 AN: 3472

East Asian (EAS) AF: 0.595 AC: 3077 AN: 5168

South Asian (SAS) AF: 0.604 AC: 2911 AN: 4822

European-Finnish (FIN) AF: 0.393 AC: 4151 AN: 10564

Middle Eastern (MID) AF: 0.582 AC: 170 AN: 292

European-Non Finnish (NFE) AF: 0.477 AC: 32433 AN: 67956

Other (OTH) AF: 0.548 AC: 1158 AN: 2112

Alfa AF: 0.508 Hom.: 42065

Bravo AF: 0.551

Asia WGS AF: 0.586 AC: 2040 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	9.1
DANN	Benign	0.49
PhyloP100		-0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs2238777; hg19: chr22-19758228;