chr22-19766780-C-T

Variant names:

• chr22-19766780-C-T
• rs72646968
• NM_001379200.1:c.1428C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_001379200.1(TBX1):​c.1428C>T​(p.Ala476Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000675 in 1,333,480 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000067 (0 hom.)
• Consequence: TBX1 NM_001379200.1 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.83
• Publications: 1 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 22-19766780-C-T is Benign according to our data. Variant chr22-19766780-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2183049.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.83 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX1	NM_001379200.1	c.1428C>T	p.Ala476Ala	synonymous_variant	Exon 7 of 7	ENST00000649276.2	NP_001366129.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBX1	ENST00000649276.2	c.1428C>T	p.Ala476Ala	synonymous_variant	Exon 7 of 7		NM_001379200.1	ENSP00000497003.1
TBX1	ENST00000332710.8	c.1401C>T	p.Ala467Ala	synonymous_variant	Exon 9 of 9	1		ENSP00000331791.4
TBX1	ENST00000329705.11	c.1009+778C>T		intron_variant	Intron 8 of 8	1		ENSP00000331176.7
TBX1	ENST00000359500.7	c.1009+778C>T		intron_variant	Intron 8 of 9	1		ENSP00000352483.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 101590 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000675 AC: 9 AN: 1333480 Hom.: 0 Cov.: 33 AF XY: 0.00000908 AC XY: 6 AN XY: 660552

African (AFR) AF: 0.00 AC: 0 AN: 26102

American (AMR) AF: 0.00 AC: 0 AN: 23162

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21950

East Asian (EAS) AF: 0.00 AC: 0 AN: 31860

South Asian (SAS) AF: 0.00 AC: 0 AN: 71942

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33752

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4510

European-Non Finnish (NFE) AF: 0.00000845 AC: 9 AN: 1065298

Other (OTH) AF: 0.00 AC: 0 AN: 54904

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

DiGeorge syndrome Benign:1

Jul 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Dec 22, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	1.1
DANN	Benign	0.94
PhyloP100		-2.8

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs72646968; hg19: chr22-19754303;