22-19759559-G-T

Position:

• chr22-19759559-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_080647.1(TBX1):​c.-85G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000913 in 1,424,374 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: 36)
  • Exomes 𝑓: 0.0000091 (0 hom.)
• Consequence: TBX1 NM_080647.1 5_prime_UTR_premature_start_codon_gain
• Scores: Splicing: ADA: 0.00002500
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.611

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BS2: High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBX1	NM_080647.1	c.-85G>T		5_prime_UTR_premature_start_codon_gain_variant	2/9		NP_542378.1
TBX1	NM_080646.2	c.-85G>T		5_prime_UTR_premature_start_codon_gain_variant	2/9		NP_542377.1
TBX1	NM_005992.1	c.-85G>T		5_prime_UTR_premature_start_codon_gain_variant	2/10		NP_005983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBX1	ENST00000332710	c.-85G>T		5_prime_UTR_premature_start_codon_gain_variant	2/9	1		ENSP00000331791.4
TBX1	ENST00000329705	c.-85G>T		5_prime_UTR_premature_start_codon_gain_variant	2/9	1		ENSP00000331176.7
TBX1	ENST00000359500	c.-85G>T		5_prime_UTR_premature_start_codon_gain_variant	2/10	1		ENSP00000352483.3

Frequencies

GnomAD3 genomes Cov.: 36

GnomAD4 exome AF: 0.00000913 AC: 13 AN: 1424374 Hom.: 0 Cov.: 54 AF XY: 0.00000849 AC XY: 6 AN XY: 706380

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000118

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 36

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	4.3
DANN	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000025
dbscSNV1_RF	Benign	0.17
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs737868; hg19: chr22-19747082;