22-19766613-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001379200.1(TBX1):​c.1261C>T​(p.His421Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000727 in 1,375,040 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: TBX1 NM_001379200.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.83

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 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>T	p.His421Tyr	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>T	p.His421Tyr	missense_variant	Exon 7 of 7		NM_001379200.1	ENSP00000497003.1
TBX1	ENST00000332710.8	c.1234C>T	p.His412Tyr	missense_variant	Exon 9 of 9	1		ENSP00000331791.4
TBX1	ENST00000329705.11	c.1009+611C>T		intron_variant	Intron 8 of 8	1		ENSP00000331176.7
TBX1	ENST00000359500.7	c.1009+611C>T		intron_variant	Intron 8 of 9	1		ENSP00000352483.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.27e-7 AC: 1 AN: 1375040 Hom.: 0 Cov.: 33 AF XY: 0.00000146 AC XY: 1 AN XY: 682858

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000127

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Benign	0.054
Eigen_PC	Benign	0.022
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.84	T;T
M_CAP	Pathogenic	1.0	D
MetaRNN	Uncertain	0.49	T;T
MetaSVM	Uncertain	-0.15	T
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-0.76	N;.
REVEL	Uncertain	0.36
Sift	Uncertain	0.0020	D;.
Sift4G	Benign	0.38	T;.
Vest4		0.47
MutPred		0.28		Gain of phosphorylation at H412 (P = 0.0092);.;
MVP		0.75
MPC		1.6
ClinPred		0.97	D
GERP RS		3.5
gMVP		0.46

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-19754136;