22-19759605-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000332710.8(TBX1):c.-39C>T variant causes a 5 prime UTR 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 ENST00000332710.8 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.11

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 -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. Variant chr22-19759605-C-T is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 138 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX1	NM_005992.1	c.-39C>T		5_prime_UTR_variant	2/10
TBX1	NM_080646.2	c.-39C>T		5_prime_UTR_variant	2/9
TBX1	NM_080647.1	c.-39C>T		5_prime_UTR_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX1	ENST00000329705.11	c.-39C>T		5_prime_UTR_variant	2/9	1		A2
TBX1	ENST00000332710.8	c.-39C>T		5_prime_UTR_variant	2/9	1		P2
TBX1	ENST00000359500.7	c.-39C>T		5_prime_UTR_variant	2/10	1		A2

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

GnomAD3 exomes AF: 0.00194 AC: 466 AN: 240380 Hom.: 5 AF XY: 0.00247 AC XY: 324 AN XY: 131240

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 SAS exome AF: 0.00864

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

Gnomad4 AFR exome AF: 0.000240

Gnomad4 AMR exome AF: 0.000539

Gnomad4 ASJ exome AF: 0.000154

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00844

Gnomad4 FIN exome AF: 0.0000195

Gnomad4 NFE exome AF: 0.00133

Gnomad4 OTH exome AF: 0.00209

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

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000326

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00869

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00123

Gnomad4 OTH AF: 0.00

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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	TBX1: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 26, 2016

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 08, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
Cadd	Benign	10
Dann	Benign	0.85

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

Publications

LitVar

Other links and lift over

dbSNP: rs72646950; hg19: chr22-19747128;