X-80022289-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001109878.2(TBX22):c.20C>A(p.Ala7Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: TBX22 NM_001109878.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.85

Genes affected

TBX22 (HGNC:11600): (T-box transcription factor 22) 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. Mutations in this gene have been associated with the inherited X-linked disorder, Cleft palate with ankyloglossia, and it is believed to play a major role in human palatogenesis. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.897

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX22	NM_001109878.2	c.20C>A	p.Ala7Glu	missense_variant	2/9	ENST00000373296.8
TBX22	NM_016954.2	c.20C>A	p.Ala7Glu	missense_variant	1/8
TBX22	NM_001109879.2	c.-337C>A		5_prime_UTR_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX22	ENST00000373296.8	c.20C>A	p.Ala7Glu	missense_variant	2/9	5	NM_001109878.2	P1
TBX22	ENST00000373294.8	c.20C>A	p.Ala7Glu	missense_variant	1/8	1		P1
TBX22	ENST00000476373.1	n.141C>A		non_coding_transcript_exon_variant	2/2	3
TBX22	ENST00000626498.2	c.20C>A	p.Ala7Glu	missense_variant, NMD_transcript_variant	2/9	2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 17, 2019

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.40	T;T
FATHMM_MKL	Uncertain	0.85	D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Uncertain	2.6	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;D
Vest4		0.73
MutPred		0.47		Loss of MoRF binding (P = 0.0345);Loss of MoRF binding (P = 0.0345);
MVP		0.91
MPC		0.71
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.85
gMVP		0.85

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: chrX-79277788;