22-19761255-G-T

Variant names:

• chr22-19761255-G-T
• rs1445910672
• NM_001379200.1:c.412G>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001379200.1(TBX1):​c.412G>T​(p.Glu138*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000707 in 1,413,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: TBX1 NM_001379200.1 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.50
• Publications: 8 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX1	NM_001379200.1	c.412G>T	p.Glu138*	stop_gained	Exon 1 of 7	ENST00000649276.2	NP_001366129.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBX1	ENST00000649276.2	c.412G>T	p.Glu138*	stop_gained	Exon 1 of 7		NM_001379200.1	ENSP00000497003.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 223822 AF XY: 0.00

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: 7.07e-7 AC: 1 AN: 1413866 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 703870

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 29648

American (AMR) AF: 0.00 AC: 0 AN: 41482

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24344

East Asian (EAS) AF: 0.00 AC: 0 AN: 35228

South Asian (SAS) AF: 0.00 AC: 0 AN: 83318

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51534

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4416

European-Non Finnish (NFE) AF: 9.21e-7 AC: 1 AN: 1086312

Other (OTH) AF: 0.00 AC: 0 AN: 57584

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	48
DANN	Uncertain	1.0
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		9.5
Vest4		0.81
GERP RS		2.9
PromoterAI		-0.22	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Mutation Taster		=1/199	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1445910672; hg19: chr22-19748778;