chr22-19759559-G-C

Variant names:

• chr22-19759559-G-C
• rs737868
• ENST00000332710.8:c.-85G>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 20 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=-0.71).
• BP6: Variant 22-19759559-G-C is Benign according to our data. Variant chr22-19759559-G-C is described in ClinVar as Benign. ClinVar VariationId is 1294260.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.673 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080647.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX1	NM_080647.1		c.-85G>C		splice_region	Exon 2 of 9	NP_542378.1	O43435-3
	TBX1	NM_080646.2		c.-85G>C		splice_region	Exon 2 of 9	NP_542377.1	O43435-1
	TBX1	NM_005992.1		c.-85G>C		splice_region	Exon 2 of 10	NP_005983.1	O43435-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX1	ENST00000332710.8	TSL:1	c.-85G>C		splice_region	Exon 2 of 9	ENSP00000331791.4	O43435-3
	TBX1	ENST00000329705.11	TSL:1	c.-85G>C		splice_region	Exon 2 of 9	ENSP00000331176.7	O43435-1
	TBX1	ENST00000359500.7	TSL:1	c.-85G>C		splice_region	Exon 2 of 10	ENSP00000352483.3	O43435-2

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

African (AFR) AF: 0.644 AC: 20873 AN: 32436

American (AMR) AF: 0.560 AC: 22543 AN: 40236

Ashkenazi Jewish (ASJ) AF: 0.691 AC: 17654 AN: 25544

East Asian (EAS) AF: 0.504 AC: 18719 AN: 37138

South Asian (SAS) AF: 0.697 AC: 57251 AN: 82130

European-Finnish (FIN) AF: 0.605 AC: 27111 AN: 44836

Middle Eastern (MID) AF: 0.604 AC: 3392 AN: 5614

European-Non Finnish (NFE) AF: 0.660 AC: 724542 AN: 1097002

Other (OTH) AF: 0.649 AC: 38354 AN: 59098

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

African (AFR) AF: 0.641 AC: 26619 AN: 41556

American (AMR) AF: 0.591 AC: 9050 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.694 AC: 2410 AN: 3472

East Asian (EAS) AF: 0.556 AC: 2872 AN: 5166

South Asian (SAS) AF: 0.692 AC: 3339 AN: 4824

European-Finnish (FIN) AF: 0.600 AC: 6358 AN: 10602

Middle Eastern (MID) AF: 0.520 AC: 153 AN: 294

European-Non Finnish (NFE) AF: 0.654 AC: 44490 AN: 67976

Other (OTH) AF: 0.632 AC: 1338 AN: 2116

Alfa AF: 0.647 Hom.: 3942

Bravo AF: 0.635

Asia WGS AF: 0.614 AC: 2138 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	3.8
DANN	Benign	0.66
PhyloP100		-0.61
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs737868; hg19: chr22-19747082; COSMIC: COSV60354723; COSMIC: COSV60354723;