22-19759605-C-T

Variant names:

• chr22-19759605-C-T
• rs72646950
• ENST00000332710.8:c.-39C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_080647.1(TBX1):​c.-39C>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 0.00156 in 1,609,706 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00091 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (8 hom.)
• Consequence: TBX1 NM_080647.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.11
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 22-19759605-C-T is Benign according to our data. Variant chr22-19759605-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 379734.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000906 (138/152374) while in subpopulation SAS AF = 0.00869 (42/4832). AF 95% confidence interval is 0.00661. There are 1 homozygotes in GnomAd4. There are 71 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 138 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX1	NM_080647.1	c.-39C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 9		NP_542378.1
TBX1	NM_080646.2	c.-39C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 9		NP_542377.1
TBX1	NM_005992.1	c.-39C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 10		NP_005983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBX1	ENST00000332710.8	c.-39C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 9	1		ENSP00000331791.4
TBX1	ENST00000329705.11	c.-39C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 9	1		ENSP00000331176.7
TBX1	ENST00000359500.7	c.-39C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 10	1		ENSP00000352483.3

Frequencies

GnomAD3 genomes AF: 0.000906 AC: 138 AN: 152256 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00868

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00123

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00194 AC: 466 AN: 240380 AF XY: 0.00247

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000645

Gnomad ASJ exome AF: 0.000204

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00164

Gnomad OTH exome AF: 0.00118

GnomAD4 exome AF: 0.00163 AC: 2380 AN: 1457332 Hom.: 8 Cov.: 34 AF XY: 0.00187 AC XY: 1352 AN XY: 724886

African (AFR) AF: 0.000240 AC: 8 AN: 33388

American (AMR) AF: 0.000539 AC: 24 AN: 44528

Ashkenazi Jewish (ASJ) AF: 0.000154 AC: 4 AN: 26052

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39504

South Asian (SAS) AF: 0.00844 AC: 724 AN: 85742

European-Finnish (FIN) AF: 0.0000195 AC: 1 AN: 51250

Middle Eastern (MID) AF: 0.00330 AC: 19 AN: 5760

European-Non Finnish (NFE) AF: 0.00133 AC: 1473 AN: 1110888

Other (OTH) AF: 0.00209 AC: 126 AN: 60220

GnomAD4 genome AF: 0.000906 AC: 138 AN: 152374 Hom.: 1 Cov.: 33 AF XY: 0.000953 AC XY: 71 AN XY: 74512

African (AFR) AF: 0.000120 AC: 5 AN: 41590

American (AMR) AF: 0.000326 AC: 5 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00869 AC: 42 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.00123 AC: 84 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000613 Hom.: 0

Bravo AF: 0.000718

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TBX1: BS2 -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Jul 26, 2016

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

DiGeorge syndrome Benign:1

Oct 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

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	10
DANN	Benign	0.85
PhyloP100		2.1
Mutation Taster		=300/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs72646950; hg19: chr22-19747128;