22-19766613-C-G

Variant names:

• chr22-19766613-C-G
• rs985907694
• NM_001379200.1:c.1261C>G

Variant summary

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

The NM_001379200.1(TBX1):​c.1261C>G​(p.His421Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. H421N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TBX1 NM_001379200.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.83
• 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_001379200.1	c.1261C>G	p.His421Asp	missense_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.1261C>G	p.His421Asp	missense_variant	Exon 7 of 7		NM_001379200.1	ENSP00000497003.1
TBX1	ENST00000332710.8	c.1234C>G	p.His412Asp	missense_variant	Exon 9 of 9	1		ENSP00000331791.4
TBX1	ENST00000329705.11	c.1009+611C>G		intron_variant	Intron 8 of 8	1		ENSP00000331176.7
TBX1	ENST00000359500.7	c.1009+611C>G		intron_variant	Intron 8 of 9	1		ENSP00000352483.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	25
DANN	Uncertain	0.99
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.77	T;T
M_CAP	Pathogenic	1.0	D
MetaRNN	Uncertain	0.63	D;D
MetaSVM	Uncertain	0.024	D
PhyloP100		2.8
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-1.6	N;.
REVEL	Uncertain	0.59
Sift	Uncertain	0.0090	D;.
Sift4G	Benign	0.093	T;.
Vest4		0.59
MutPred		0.29		Gain of ubiquitination at K417 (P = 0.1489);.;
MVP		0.92
MPC		1.7
ClinPred		0.97	D
GERP RS		3.5
gMVP		0.52
Mutation Taster		=49/51	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: rs985907694; hg19: chr22-19754136;