rs104894943

Variant names:

• chrX-80026849-C-T
• rs104894943
• NM_001109878.2:c.779C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001109878.2(TBX22):​c.779C>T​(p.Thr260Met) 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 Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. T260T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: TBX22 NM_001109878.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.14
• Publications: 6 publications found

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]

TBX22 Gene-Disease associations (from GenCC):

• cleft palate with or without ankyloglossia, X-linked

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
• Abruzzo-Erickson syndrome

  Inheritance: XL Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, G2P

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant X-80026849-C-T is Pathogenic according to our data. Variant chrX-80026849-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 11329.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX22	NM_001109878.2	c.779C>T	p.Thr260Met	missense_variant	Exon 6 of 9	ENST00000373296.8	NP_001103348.1
TBX22	NM_016954.2	c.779C>T	p.Thr260Met	missense_variant	Exon 5 of 8		NP_058650.1
TBX22	NM_001109879.2	c.419C>T	p.Thr140Met	missense_variant	Exon 6 of 9		NP_001103349.1
TBX22	NM_001303475.1	c.419C>T	p.Thr140Met	missense_variant	Exon 4 of 7		NP_001290404.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBX22	ENST00000373296.8	c.779C>T	p.Thr260Met	missense_variant	Exon 6 of 9	5	NM_001109878.2	ENSP00000362393.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Cleft palate with ankyloglossia Pathogenic:1

Oct 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.67
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;D
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.0	H;H
PhyloP100		7.1
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-5.5	D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.95
MutPred		0.94		Gain of stability (P = 0.0341);Gain of stability (P = 0.0341);
MVP		0.94
MPC		0.67
ClinPred		1.0	D
GERP RS		3.7
Varity_R		0.94
gMVP		0.85
Mutation Taster		=23/77	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs104894943; hg19: chrX-79282348; COSMIC: COSV64785482; COSMIC: COSV64785482;