ENST00000332710.8:c.28A>G

Variant names:

• chr22-19759671-A-G
• rs1936578247
• ENST00000332710.8:c.28A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000332710.8(TBX1):​c.28A>G​(p.Met10Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TBX1 ENST00000332710.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.42
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX1	NM_080647.1	c.28A>G	p.Met10Val	missense_variant	Exon 2 of 9		NP_542378.1
TBX1	NM_080646.2	c.28A>G	p.Met10Val	missense_variant	Exon 2 of 9		NP_542377.1
TBX1	NM_005992.1	c.28A>G	p.Met10Val	missense_variant	Exon 2 of 10		NP_005983.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBX1	ENST00000332710.8	c.28A>G	p.Met10Val	missense_variant	Exon 2 of 9	1		ENSP00000331791.4
TBX1	ENST00000329705.11	c.28A>G	p.Met10Val	missense_variant	Exon 2 of 9	1		ENSP00000331176.7
TBX1	ENST00000359500.7	c.28A>G	p.Met10Val	missense_variant	Exon 2 of 10	1		ENSP00000352483.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

DiGeorge syndrome Uncertain:1

Jul 12, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals with TBX1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with valine at codon 10 of the TBX1 protein (p.Met10Val). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and valine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.23	.;T;.
Eigen	Benign	-0.17
Eigen_PC	Benign	0.025
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.54	T;T;T
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.46	T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	-0.080	N;N;N
PhyloP100		6.4
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.73	N;N;N
REVEL	Uncertain	0.48
Sift	Benign	0.36	T;T;T
Sift4G	Benign	0.61	T;T;T
Polyphen		0.30	.;B;.
Vest4		0.66
MutPred		0.21		Loss of catalytic residue at V6 (P = 0.0226);Loss of catalytic residue at V6 (P = 0.0226);Loss of catalytic residue at V6 (P = 0.0226);
MVP		0.96
MPC		1.9
ClinPred		0.64	D
GERP RS		4.8
Varity_R		0.21
gMVP		0.50
Mutation Taster		=69/31	polymorphism

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: rs1936578247; hg19: chr22-19747194;