22-19760999-CCCGCCG-CCCGCCGCCG

Variant names:

• chr22-19760999-C-CCCG
• rs886038791
• NM_001379200.1:c.170_172dupCGC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP3 BP6 BS1 BS2

The NM_001379200.1(TBX1):​c.170_172dupCGC​(p.Pro57dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000717 in 933,994 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000082 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000070 (0 hom.)
• Consequence: TBX1 NM_001379200.1 disruptive_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.41
• Publications: 0 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 -10 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001379200.1
• BP6: Variant 22-19760999-C-CCCG is Benign according to our data. Variant chr22-19760999-C-CCCG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 263404.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000825 (12/145488) while in subpopulation SAS AF = 0.000209 (1/4784). AF 95% confidence interval is 0.0000493. There are 0 homozygotes in GnomAd4. There are 9 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX1	NM_001379200.1	c.170_172dupCGC	p.Pro57dup	disruptive_inframe_insertion	Exon 1 of 7	ENST00000649276.2	NP_001366129.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBX1	ENST00000649276.2	c.170_172dupCGC	p.Pro57dup	disruptive_inframe_insertion	Exon 1 of 7		NM_001379200.1	ENSP00000497003.1

Frequencies

GnomAD3 genomes AF: 0.0000825 AC: 12 AN: 145488 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000136

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000201

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000107

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000698 AC: 55 AN: 788506 Hom.: 0 Cov.: 11 AF XY: 0.0000630 AC XY: 23 AN XY: 365226

African (AFR) AF: 0.000135 AC: 2 AN: 14846

American (AMR) AF: 0.00 AC: 0 AN: 932

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4876

East Asian (EAS) AF: 0.00 AC: 0 AN: 3358

South Asian (SAS) AF: 0.000183 AC: 3 AN: 16374

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 262

Middle Eastern (MID) AF: 0.000644 AC: 1 AN: 1552

European-Non Finnish (NFE) AF: 0.0000652 AC: 47 AN: 720538

Other (OTH) AF: 0.0000776 AC: 2 AN: 25768

GnomAD4 genome AF: 0.0000825 AC: 12 AN: 145488 Hom.: 0 Cov.: 31 AF XY: 0.000127 AC XY: 9 AN XY: 70692

African (AFR) AF: 0.0000246 AC: 1 AN: 40636

American (AMR) AF: 0.000136 AC: 2 AN: 14678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3380

East Asian (EAS) AF: 0.000201 AC: 1 AN: 4970

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8282

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 298

European-Non Finnish (NFE) AF: 0.000107 AC: 7 AN: 65558

Other (OTH) AF: 0.00 AC: 0 AN: 1998

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000453

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Sep 26, 2012

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

There is insufficient or conflicting evidence for classification of this alteration. -

DiGeorge syndrome Benign:1

Nov 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.4
Mutation Taster		=87/13	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs886038791; hg19: chr22-19748522;