rs104894946

chrX-80026711-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_001109878.2(TBX22):c.641T>C(p.Leu214Pro) variant causes a missense change involving the alteration of a conserved nucleotide. 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).

• Frequency: Genomes: not found (cov: 23)
• Consequence: TBX22 NM_001109878.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.24

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a DNA_binding_region T-box (size 187) in uniprot entity TBX22_HUMAN there are 9 pathogenic changes around while only 2 benign (82%) in NM_001109878.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant X-80026711-T-C is Pathogenic according to our data. Variant chrX-80026711-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 11334.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-80026711-T-C is described in UniProt as null. Variant chrX-80026711-T-C is described in UniProt as null.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX22	NM_001109878.2	c.641T>C	p.Leu214Pro	missense_variant	6/9	ENST00000373296.8
TBX22	NM_016954.2	c.641T>C	p.Leu214Pro	missense_variant	5/8
TBX22	NM_001109879.2	c.281T>C	p.Leu94Pro	missense_variant	6/9
TBX22	NM_001303475.1	c.281T>C	p.Leu94Pro	missense_variant	4/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX22	ENST00000373296.8	c.641T>C	p.Leu214Pro	missense_variant	6/9	5	NM_001109878.2	P1
TBX22	ENST00000373294.8	c.641T>C	p.Leu214Pro	missense_variant	5/8	1		P1
TBX22	ENST00000626877.1	n.520T>C		non_coding_transcript_exon_variant	4/7	1
TBX22	ENST00000626498.2	c.*253T>C		3_prime_UTR_variant, NMD_transcript_variant	6/9	2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Cleft palate with ankyloglossia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 15, 2002

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.68	D
BayesDel_noAF	Pathogenic	0.74
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D;D
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.3	H;H
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.9	D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.99
MutPred		0.93		Gain of disorder (P = 0.0067);Gain of disorder (P = 0.0067);
MVP		0.99
MPC		0.85
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.99
gMVP		0.95

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

LitVar

Other links and lift over

dbSNP: rs104894946; hg19: chrX-79282210;