rs28939675

Variant names:

• chr22-19763273-T-A
• rs28939675
• NM_001379200.1:c.470T>A

Your query was ambiguous. Multiple possible variants found:

• chr22-19763273-T-A
• chr22-19763273-T-C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP5

The NM_001379200.1(TBX1):​c.470T>A​(p.Phe157Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F157S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TBX1 NM_001379200.1 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.13
• Publications: 15 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-19763273-T-A is Pathogenic according to our data. Variant chr22-19763273-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 7563.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001379200.1. 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_001379200.1	MANE Select	c.470T>A	p.Phe157Tyr	missense	Exon 2 of 7	NP_001366129.1	A0A3B3IS18
	TBX1	NM_080647.1		c.443T>A	p.Phe148Tyr	missense	Exon 4 of 9	NP_542378.1	O43435-3
	TBX1	NM_080646.2		c.443T>A	p.Phe148Tyr	missense	Exon 4 of 9	NP_542377.1	O43435-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX1	ENST00000649276.2	MANE Select	c.470T>A	p.Phe157Tyr	missense	Exon 2 of 7	ENSP00000497003.1	A0A3B3IS18
	TBX1	ENST00000332710.8	TSL:1	c.443T>A	p.Phe148Tyr	missense	Exon 4 of 9	ENSP00000331791.4	O43435-3
	TBX1	ENST00000329705.11	TSL:1	c.443T>A	p.Phe148Tyr	missense	Exon 4 of 9	ENSP00000331176.7	O43435-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Conotruncal anomaly face syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	0.50	N
PhyloP100		4.1
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.83	N
REVEL	Uncertain	0.47
Sift	Benign	0.35	T
Sift4G	Benign	0.54	T
Polyphen		0.011	B
Vest4		0.70
MutPred		0.68		Loss of ubiquitination at K146 (P = 0.0665)
MVP		0.93
MPC		1.2
ClinPred		0.83	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.59
gMVP		0.57
Mutation Taster		=2/98	disease causing (ClinVar)

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: rs28939675; hg19: chr22-19750796;