chr22-19759510-C-G

Variant names:

• chr22-19759510-C-G
• rs72646948
• ENST00000332710.8:c.-86-48C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The ENST00000332710.8(TBX1):​c.-86-48C>G variant causes a intron change. The variant allele was found at a frequency of 0.0135 in 1,514,532 control chromosomes in the GnomAD database, including 182 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0079 (11 hom., cov: 35)
  • Exomes 𝑓: 0.014 (171 hom.)
• Consequence: TBX1 ENST00000332710.8 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.22
• Publications: 3 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.23).
• BP6: Variant 22-19759510-C-G is Benign according to our data. Variant chr22-19759510-C-G is described in ClinVar as [Benign]. Clinvar id is 2652866.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00787 (1199/152340) while in subpopulation NFE AF = 0.0143 (970/68022). AF 95% confidence interval is 0.0135. There are 11 homozygotes in GnomAd4. There are 523 alleles in the male GnomAd4 subpopulation. Median coverage is 35. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1199 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX1	NM_080647.1	c.-86-48C>G		intron_variant	Intron 1 of 8		NP_542378.1
TBX1	NM_080646.2	c.-86-48C>G		intron_variant	Intron 1 of 8		NP_542377.1
TBX1	NM_005992.1	c.-86-48C>G		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.-86-48C>G		intron_variant	Intron 1 of 8	1		ENSP00000331791.4
TBX1	ENST00000329705.11	c.-86-48C>G		intron_variant	Intron 1 of 8	1		ENSP00000331176.7
TBX1	ENST00000359500.7	c.-86-48C>G		intron_variant	Intron 1 of 9	1		ENSP00000352483.3

Frequencies

GnomAD3 genomes AF: 0.00788 AC: 1200 AN: 152222 Hom.: 11 Cov.: 35

Gnomad AFR AF: 0.00222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00517

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00348

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0143

Gnomad OTH AF: 0.00669

GnomAD4 exome AF: 0.0141 AC: 19215 AN: 1362192 Hom.: 171 Cov.: 29 AF XY: 0.0136 AC XY: 9105 AN XY: 670452

African (AFR) AF: 0.00204 AC: 61 AN: 29882

American (AMR) AF: 0.00447 AC: 151 AN: 33810

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 55 AN: 23850

East Asian (EAS) AF: 0.00 AC: 0 AN: 34586

South Asian (SAS) AF: 0.000805 AC: 62 AN: 76992

European-Finnish (FIN) AF: 0.00380 AC: 132 AN: 34780

Middle Eastern (MID) AF: 0.00168 AC: 7 AN: 4162

European-Non Finnish (NFE) AF: 0.0170 AC: 18136 AN: 1067462

Other (OTH) AF: 0.0108 AC: 611 AN: 56668

GnomAD4 genome AF: 0.00787 AC: 1199 AN: 152340 Hom.: 11 Cov.: 35 AF XY: 0.00702 AC XY: 523 AN XY: 74496

African (AFR) AF: 0.00221 AC: 92 AN: 41584

American (AMR) AF: 0.00510 AC: 78 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00348 AC: 37 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0143 AC: 970 AN: 68022

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

Alfa AF: 0.00937 Hom.: 3

Bravo AF: 0.00794

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Mar 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TBX1: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Benign	0.95
PhyloP100		4.2
Mutation Taster		=85/15	polymorphism

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: rs72646948; hg19: chr22-19747033;