22-19759559-G-C

Position:

• chr22-19759559-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_080647.1(TBX1):​c.-85G>C variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.652 in 1,576,252 control chromosomes in the GnomAD database, including 336,463 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (31075 hom., cov: 36)
  • Exomes 𝑓: 0.65 (305388 hom.)
• Consequence: TBX1 NM_080647.1 splice_region
• Scores: Splicing: ADA: 0.00002533
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.611

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=-0.71).
• BP6: Variant 22-19759559-G-C is Benign according to our data. Variant chr22-19759559-G-C is described in ClinVar as [Benign]. Clinvar id is 1294260.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-19759559-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.673 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBX1	NM_080647.1	c.-85G>C		splice_region_variant	2/9		NP_542378.1
TBX1	NM_080646.2	c.-85G>C		splice_region_variant	2/9		NP_542377.1
TBX1	NM_005992.1	c.-85G>C		splice_region_variant	2/10		NP_005983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBX1	ENST00000332710.8	c.-85G>C		splice_region_variant	2/9	1		ENSP00000331791.4
TBX1	ENST00000329705.11	c.-85G>C		splice_region_variant	2/9	1		ENSP00000331176.7
TBX1	ENST00000359500.7	c.-85G>C		splice_region_variant	2/10	1		ENSP00000352483.3

Frequencies

GnomAD3 genomes AF: 0.638 AC: 97058 AN: 152100 Hom.: 31035 Cov.: 36

Gnomad AFR AF: 0.640

Gnomad AMI AF: 0.582

Gnomad AMR AF: 0.591

Gnomad ASJ AF: 0.694

Gnomad EAS AF: 0.556

Gnomad SAS AF: 0.693

Gnomad FIN AF: 0.600

Gnomad MID AF: 0.532

Gnomad NFE AF: 0.654

Gnomad OTH AF: 0.633

GnomAD4 exome AF: 0.653 AC: 930439 AN: 1424034 Hom.: 305388 Cov.: 54 AF XY: 0.655 AC XY: 462790 AN XY: 706170

Gnomad4 AFR exome AF: 0.644

Gnomad4 AMR exome AF: 0.560

Gnomad4 ASJ exome AF: 0.691

Gnomad4 EAS exome AF: 0.504

Gnomad4 SAS exome AF: 0.697

Gnomad4 FIN exome AF: 0.605

Gnomad4 NFE exome AF: 0.660

Gnomad4 OTH exome AF: 0.649

GnomAD4 genome AF: 0.638 AC: 97159 AN: 152218 Hom.: 31075 Cov.: 36 AF XY: 0.635 AC XY: 47230 AN XY: 74418

Gnomad4 AFR AF: 0.641

Gnomad4 AMR AF: 0.591

Gnomad4 ASJ AF: 0.694

Gnomad4 EAS AF: 0.556

Gnomad4 SAS AF: 0.692

Gnomad4 FIN AF: 0.600

Gnomad4 NFE AF: 0.654

Gnomad4 OTH AF: 0.632

Alfa AF: 0.647 Hom.: 3942

Bravo AF: 0.635

Asia WGS AF: 0.614 AC: 2138 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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	3.8
DANN	Benign	0.66

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000025
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.0		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: rs737868; hg19: chr22-19747082; COSMIC: COSV60354723; COSMIC: COSV60354723;