ENST00000332710.8:c.-86-2A>C

Variant names:

• chr22-19759556-A-C
• rs1936571734
• ENST00000332710.8:c.-86-2A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PVS1_Moderate PM2 BS2

The ENST00000332710.8(TBX1):​c.-86-2A>C variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00000352 in 1,420,776 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: TBX1 ENST00000332710.8 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.45
• 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.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.08064516 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.5, offset of 29, new splice context is: cggagcgcaccgcccaccAGggc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX1	NM_080647.1	c.-86-2A>C		splice_acceptor_variant, intron_variant	Intron 1 of 8		NP_542378.1
TBX1	NM_080646.2	c.-86-2A>C		splice_acceptor_variant, intron_variant	Intron 1 of 8		NP_542377.1
TBX1	NM_005992.1	c.-86-2A>C		splice_acceptor_variant, intron_variant	Intron 1 of 9		NP_005983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBX1	ENST00000332710.8	c.-86-2A>C		splice_acceptor_variant, intron_variant	Intron 1 of 8	1		ENSP00000331791.4
TBX1	ENST00000329705.11	c.-86-2A>C		splice_acceptor_variant, intron_variant	Intron 1 of 8	1		ENSP00000331176.7
TBX1	ENST00000359500.7	c.-86-2A>C		splice_acceptor_variant, intron_variant	Intron 1 of 9	1		ENSP00000352483.3

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome AF: 0.00000352 AC: 5 AN: 1420776 Hom.: 0 Cov.: 29 AF XY: 0.00000142 AC XY: 1 AN XY: 704228

African (AFR) AF: 0.00 AC: 0 AN: 32336

American (AMR) AF: 0.00 AC: 0 AN: 39770

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25476

East Asian (EAS) AF: 0.00 AC: 0 AN: 36918

South Asian (SAS) AF: 0.00 AC: 0 AN: 81706

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44298

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5582

European-Non Finnish (NFE) AF: 0.00000456 AC: 5 AN: 1095732

Other (OTH) AF: 0.00 AC: 0 AN: 58958

GnomAD4 genome Cov.: 35

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	15
DANN	Uncertain	0.99
PhyloP100		6.4

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.90		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.90		Position offset: 2

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

Other links and lift over

dbSNP: rs1936571734; hg19: chr22-19747079;