22-19777659-G-A

Variant names:

• chr22-19777659-G-A
• rs4819843
• ENST00000329705.11:c.1010-1561G>A

Variant summary

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

The NM_080646.2(TBX1):​c.1010-1561G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.185 in 151,978 control chromosomes in the GnomAD database, including 2,766 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 0.19 (2766 hom., cov: 31)
• Consequence: TBX1 NM_080646.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.595
• Publications: 6 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, 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.35 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080646.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX1	NM_080646.2		c.1010-1561G>A		intron	N/A	NP_542377.1	O43435-1
	TBX1	NM_005992.1		c.1010-5254G>A		intron	N/A	NP_005983.1	O43435-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX1	ENST00000329705.11	TSL:1	c.1010-1561G>A		intron	N/A	ENSP00000331176.7	O43435-1
	TBX1	ENST00000359500.7	TSL:1	c.1010-5254G>A		intron	N/A	ENSP00000352483.3	O43435-2

Frequencies

GnomAD3 genomes AF: 0.185 AC: 28130 AN: 151860 Hom.: 2759 Cov.: 31

Gnomad AFR AF: 0.136

Gnomad AMI AF: 0.241

Gnomad AMR AF: 0.232

Gnomad ASJ AF: 0.200

Gnomad EAS AF: 0.120

Gnomad SAS AF: 0.366

Gnomad FIN AF: 0.210

Gnomad MID AF: 0.277

Gnomad NFE AF: 0.191

Gnomad OTH AF: 0.208

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

GnomAD4 genome AF: 0.185 AC: 28160 AN: 151978 Hom.: 2766 Cov.: 31 AF XY: 0.190 AC XY: 14107 AN XY: 74278

African (AFR) AF: 0.136 AC: 5631 AN: 41430

American (AMR) AF: 0.233 AC: 3546 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.200 AC: 696 AN: 3472

East Asian (EAS) AF: 0.120 AC: 620 AN: 5184

South Asian (SAS) AF: 0.364 AC: 1752 AN: 4808

European-Finnish (FIN) AF: 0.210 AC: 2209 AN: 10540

Middle Eastern (MID) AF: 0.274 AC: 80 AN: 292

European-Non Finnish (NFE) AF: 0.191 AC: 12965 AN: 67982

Other (OTH) AF: 0.209 AC: 442 AN: 2112

Alfa AF: 0.184 Hom.: 2051

Bravo AF: 0.184

Asia WGS AF: 0.242 AC: 842 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.95
DANN	Benign	0.64
PhyloP100		-0.59
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: rs4819843; hg19: chr22-19765182;