22-19759519-C-T

Position:

• chr22-19759519-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_080647.1(TBX1):​c.-86-39C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0049 in 1,533,824 control chromosomes in the GnomAD database, including 360 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (179 hom., cov: 35)
  • Exomes 𝑓: 0.0026 (181 hom.)
• Consequence: TBX1 NM_080647.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.23

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.22).
• BP6: Variant 22-19759519-C-T is Benign according to our data. Variant chr22-19759519-C-T is described in ClinVar as [Benign]. Clinvar id is 1264784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0887 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBX1	NM_080647.1	c.-86-39C>T		intron_variant			NP_542378.1
TBX1	NM_080646.2	c.-86-39C>T		intron_variant			NP_542377.1
TBX1	NM_005992.1	c.-86-39C>T		intron_variant			NP_005983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBX1	ENST00000332710.8	c.-86-39C>T		intron_variant		1		ENSP00000331791.4
TBX1	ENST00000329705.11	c.-86-39C>T		intron_variant		1		ENSP00000331176.7
TBX1	ENST00000359500.7	c.-86-39C>T		intron_variant		1		ENSP00000352483.3

Frequencies

GnomAD3 genomes AF: 0.0259 AC: 3949 AN: 152222 Hom.: 178 Cov.: 35

Gnomad AFR AF: 0.0913

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00752

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.0138

GnomAD4 exome AF: 0.00258 AC: 3558 AN: 1381484 Hom.: 181 Cov.: 29 AF XY: 0.00226 AC XY: 1539 AN XY: 681524

Gnomad4 AFR exome AF: 0.0941

Gnomad4 AMR exome AF: 0.00428

Gnomad4 ASJ exome AF: 0.0000808

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000114

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000132

Gnomad4 OTH exome AF: 0.00505

GnomAD4 genome AF: 0.0260 AC: 3956 AN: 152340 Hom.: 179 Cov.: 35 AF XY: 0.0249 AC XY: 1854 AN XY: 74498

Gnomad4 AFR AF: 0.0912

Gnomad4 AMR AF: 0.00751

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.0217 Hom.: 11

Bravo AF: 0.0291

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 26, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.22
CADD	Benign	23
DANN	Uncertain	0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs41299457; hg19: chr22-19747042;