22-19759638-GCAGGGATGCA-G

Position:

• chr22-19759638-GCAGGGATGCA-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_080647.1(TBX1):​c.-4_6delAGGGATGCAC​(p.Met1fs) variant causes a frameshift, start lost change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TBX1 NM_080647.1 frameshift, start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.75

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 12 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBX1	NM_080647.1	c.-4_6delAGGGATGCAC	p.Met1fs	frameshift_variant, start_lost	2/9		NP_542378.1
TBX1	NM_080646.2	c.-4_6delAGGGATGCAC	p.Met1fs	frameshift_variant, start_lost	2/9		NP_542377.1
TBX1	NM_005992.1	c.-4_6delAGGGATGCAC	p.Met1fs	frameshift_variant, start_lost	2/10		NP_005983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBX1	ENST00000332710.8	c.-4_6delAGGGATGCAC	p.Met1fs	frameshift_variant, start_lost	2/9	1		ENSP00000331791.4
TBX1	ENST00000329705.11	c.-4_6delAGGGATGCAC	p.Met1fs	frameshift_variant, start_lost	2/9	1		ENSP00000331176.7
TBX1	ENST00000359500.7	c.-4_6delAGGGATGCAC	p.Met1fs	frameshift_variant, start_lost	2/10	1		ENSP00000352483.3

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

DiGeorge syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 17, 2022

This variant has not been reported in the literature in individuals affected with TBX1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the TBX1 mRNA. The next in-frame methionine is located at codon 10. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-19747161;