chr22-19763274-C-G

Variant names:

• chr22-19763274-C-G
• rs139776757
• NM_001379200.1:c.471C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The NM_001379200.1(TBX1):​c.471C>G​(p.Phe157Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F157Y) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TBX1 NM_001379200.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.49
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.33391154).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX1	NM_001379200.1	MANE Select	c.471C>G	p.Phe157Leu	missense	Exon 2 of 7	NP_001366129.1
	TBX1	NM_080647.1		c.444C>G	p.Phe148Leu	missense	Exon 4 of 9	NP_542378.1
	TBX1	NM_080646.2		c.444C>G	p.Phe148Leu	missense	Exon 4 of 9	NP_542377.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX1	ENST00000649276.2	MANE Select	c.471C>G	p.Phe157Leu	missense	Exon 2 of 7	ENSP00000497003.1
	TBX1	ENST00000332710.8	TSL:1	c.444C>G	p.Phe148Leu	missense	Exon 4 of 9	ENSP00000331791.4
	TBX1	ENST00000329705.11	TSL:1	c.444C>G	p.Phe148Leu	missense	Exon 4 of 9	ENSP00000331176.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.081	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	10
DANN	Benign	0.97
DEOGEN2	Uncertain	0.63	D
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.75	N
PhyloP100		-1.5
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.46
Sift	Benign	0.34	T
Sift4G	Benign	0.49	T
Polyphen		0.0010	B
Vest4		0.67
MutPred		0.56		Loss of ubiquitination at K146 (P = 0.0607)
MVP		0.86
MPC		0.64
ClinPred		0.56	D
GERP RS		-4.0
Varity_R		0.53
gMVP		0.69
Mutation Taster		=13/87	disease causing

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: rs139776757; hg19: chr22-19750797;