rs28935177

Positions:

• chrX-80026860-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001109878.2(TBX22):​c.790A>T​(p.Asn264Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,989 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 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)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: TBX22 NM_001109878.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.43

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 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant X-80026860-A-T is Pathogenic according to our data. Variant chrX-80026860-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 11336.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-80026860-A-T is described in UniProt as null. Variant chrX-80026860-A-T is described in UniProt as null. Variant chrX-80026860-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBX22	NM_001109878.2	c.790A>T	p.Asn264Tyr	missense_variant	6/9	ENST00000373296.8	NP_001103348.1
TBX22	NM_016954.2	c.790A>T	p.Asn264Tyr	missense_variant	5/8		NP_058650.1
TBX22	NM_001109879.2	c.430A>T	p.Asn144Tyr	missense_variant	6/9		NP_001103349.1
TBX22	NM_001303475.1	c.430A>T	p.Asn144Tyr	missense_variant	4/7		NP_001290404.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBX22	ENST00000373296.8	c.790A>T	p.Asn264Tyr	missense_variant	6/9	5	NM_001109878.2	ENSP00000362393.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097989 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 363371

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

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

Jan 01, 2004

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.93	D;D
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.3	H;H
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-7.3	D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.99
MutPred		0.89		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.96
MPC		0.73
ClinPred		1.0	D
GERP RS		3.7
Varity_R		0.99
gMVP		0.92

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: rs28935177; hg19: chrX-79282359;