X-80022270-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001109878.2(TBX22):c.1A>G(p.Met1?) variant causes a start lost, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: TBX22 NM_001109878.2 start_lost, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.54

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX22	NM_001109878.2	c.1A>G	p.Met1?	start_lost, splice_region_variant	2/9	ENST00000373296.8
TBX22	NM_016954.2	c.1A>G	p.Met1?	start_lost	1/8
TBX22	NM_001109879.2	c.-356A>G		splice_region_variant, 5_prime_UTR_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX22	ENST00000373294.8	c.1A>G	p.Met1?	start_lost	1/8	1		P1
TBX22	ENST00000373296.8	c.1A>G	p.Met1?	start_lost, splice_region_variant	2/9	5	NM_001109878.2	P1
TBX22	ENST00000476373.1	n.122A>G		splice_region_variant, non_coding_transcript_exon_variant	2/2	3
TBX22	ENST00000626498.2	c.1A>G	p.Met1?	start_lost, splice_region_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

TBX22-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 04, 2022

The TBX22 c.1A>G variant is predicted to disrupt the translation initiation site (Start loss). To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
Cadd	Benign	19
Dann	Benign	0.95
DEOGEN2	Benign	0.12	T;T
FATHMM_MKL	Benign	0.71	D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Benign	-0.46	T
MutationTaster	Benign	1.0	D;D;D
PROVEAN	Benign	-1.0	N;N
REVEL	Uncertain	0.64
Sift	Benign	0.43	T;T
Sift4G	Benign	0.24	T;T
Polyphen		0.30	B;B
Vest4		0.89
MutPred		0.95		Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);
MVP		0.99
ClinPred		0.98	D
GERP RS		4.5
Varity_R		0.37
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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-79277769;