22-19759380-A-T

Variant names:

• chr22-19759380-A-T
• rs737867
• ENST00000332710.8:c.-86-178A>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_080647.1(TBX1):​c.-86-178A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.643 in 627,472 control chromosomes in the GnomAD database, including 131,250 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.59 (26790 hom., cov: 34)
  • Exomes 𝑓: 0.66 (104460 hom.)
• Consequence: TBX1 NM_080647.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.638
• Publications: 1 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 22-19759380-A-T is Benign according to our data. Variant chr22-19759380-A-T is described in ClinVar as [Benign]. Clinvar id is 1290981.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.672 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX1	NM_080647.1	c.-86-178A>T		intron_variant	Intron 1 of 8		NP_542378.1
TBX1	NM_080646.2	c.-86-178A>T		intron_variant	Intron 1 of 8		NP_542377.1
TBX1	NM_005992.1	c.-86-178A>T		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.-86-178A>T		intron_variant	Intron 1 of 8	1		ENSP00000331791.4
TBX1	ENST00000329705.11	c.-86-178A>T		intron_variant	Intron 1 of 8	1		ENSP00000331176.7
TBX1	ENST00000359500.7	c.-86-178A>T		intron_variant	Intron 1 of 9	1		ENSP00000352483.3

Frequencies

GnomAD3 genomes AF: 0.588 AC: 89296 AN: 151884 Hom.: 26767 Cov.: 34

Gnomad AFR AF: 0.462

Gnomad AMI AF: 0.584

Gnomad AMR AF: 0.572

Gnomad ASJ AF: 0.694

Gnomad EAS AF: 0.581

Gnomad SAS AF: 0.692

Gnomad FIN AF: 0.600

Gnomad MID AF: 0.519

Gnomad NFE AF: 0.654

Gnomad OTH AF: 0.594

GnomAD4 exome AF: 0.660 AC: 313976 AN: 475474 Hom.: 104460 AF XY: 0.660 AC XY: 147421 AN XY: 223198

African (AFR) AF: 0.461 AC: 4077 AN: 8844

American (AMR) AF: 0.588 AC: 327 AN: 556

Ashkenazi Jewish (ASJ) AF: 0.689 AC: 2011 AN: 2920

East Asian (EAS) AF: 0.572 AC: 1138 AN: 1990

South Asian (SAS) AF: 0.704 AC: 6645 AN: 9436

European-Finnish (FIN) AF: 0.648 AC: 105 AN: 162

Middle Eastern (MID) AF: 0.620 AC: 599 AN: 966

European-Non Finnish (NFE) AF: 0.664 AC: 288963 AN: 435158

Other (OTH) AF: 0.655 AC: 10111 AN: 15442

GnomAD4 genome AF: 0.588 AC: 89369 AN: 151998 Hom.: 26790 Cov.: 34 AF XY: 0.586 AC XY: 43572 AN XY: 74294

African (AFR) AF: 0.463 AC: 19205 AN: 41486

American (AMR) AF: 0.573 AC: 8754 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.694 AC: 2404 AN: 3466

East Asian (EAS) AF: 0.581 AC: 2978 AN: 5124

South Asian (SAS) AF: 0.692 AC: 3341 AN: 4828

European-Finnish (FIN) AF: 0.600 AC: 6356 AN: 10590

Middle Eastern (MID) AF: 0.507 AC: 149 AN: 294

European-Non Finnish (NFE) AF: 0.654 AC: 44400 AN: 67908

Other (OTH) AF: 0.594 AC: 1253 AN: 2108

Alfa AF: 0.615 Hom.: 3617

Bravo AF: 0.578

Asia WGS AF: 0.608 AC: 2115 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	11
DANN	Benign	0.63
PhyloP100		0.64
Mutation Taster		=100/0	polymorphism (auto)

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: rs737867; hg19: chr22-19746903;