22-19759510-C-T

Variant names:

• chr22-19759510-C-T
• rs72646948
• ENST00000332710.8:c.-86-48C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_080647.1(TBX1):​c.-86-48C>T variant causes a intron change. The variant allele was found at a frequency of 0.00000147 in 1,362,212 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: 35)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: TBX1 NM_080647.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.22
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.2).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080647.1. 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_080647.1		c.-86-48C>T		intron	N/A	NP_542378.1	O43435-3
	TBX1	NM_080646.2		c.-86-48C>T		intron	N/A	NP_542377.1	O43435-1
	TBX1	NM_005992.1		c.-86-48C>T		intron	N/A	NP_005983.1	O43435-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX1	ENST00000332710.8	TSL:1	c.-86-48C>T		intron	N/A	ENSP00000331791.4	O43435-3
	TBX1	ENST00000329705.11	TSL:1	c.-86-48C>T		intron	N/A	ENSP00000331176.7	O43435-1
	TBX1	ENST00000359500.7	TSL:1	c.-86-48C>T		intron	N/A	ENSP00000352483.3	O43435-2

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome AF: 0.00000147 AC: 2 AN: 1362212 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 670462

African (AFR) AF: 0.00 AC: 0 AN: 29882

American (AMR) AF: 0.00 AC: 0 AN: 33814

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23850

East Asian (EAS) AF: 0.00 AC: 0 AN: 34586

South Asian (SAS) AF: 0.0000130 AC: 1 AN: 76994

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34780

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4162

European-Non Finnish (NFE) AF: 9.37e-7 AC: 1 AN: 1067476

Other (OTH) AF: 0.00 AC: 0 AN: 56668

GnomAD4 genome Cov.: 35

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.20
CADD	Benign	22
DANN	Uncertain	0.98
PhyloP100		4.2

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

Other links and lift over

dbSNP: rs72646948; hg19: chr22-19747033;