rs1395804892

Variant names:

• chrX-80022322-G-T
• rs1395804892
• NM_001109878.2:c.53G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001109878.2(TBX22):​c.53G>T​(p.Arg18Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000899 in 111,260 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 22)
• Consequence: TBX22 NM_001109878.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.598
• Publications: 0 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: Orphanet, ClinGen, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• Abruzzo-Erickson syndrome

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

ENSG00000300464 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001109878.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX22	NM_001109878.2	MANE Select	c.53G>T	p.Arg18Ile	missense	Exon 2 of 9	NP_001103348.1	Q9Y458-1
	TBX22	NM_016954.2		c.53G>T	p.Arg18Ile	missense	Exon 1 of 8	NP_058650.1	Q9Y458-1
	TBX22	NM_001109879.2		c.-304G>T		5_prime_UTR	Exon 2 of 9	NP_001103349.1	Q9Y458-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX22	ENST00000373296.8	TSL:5 MANE Select	c.53G>T	p.Arg18Ile	missense	Exon 2 of 9	ENSP00000362393.3	Q9Y458-1
	TBX22	ENST00000373294.8	TSL:1	c.53G>T	p.Arg18Ile	missense	Exon 1 of 8	ENSP00000362390.5	Q9Y458-1
	TBX22	ENST00000924637.1		c.53G>T	p.Arg18Ile	missense	Exon 1 of 8	ENSP00000594696.1

Frequencies

GnomAD3 genomes AF: 0.00000899 AC: 1 AN: 111260 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000952

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000899 AC: 1 AN: 111260 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33476

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30529

American (AMR) AF: 0.0000952 AC: 1 AN: 10504

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2645

East Asian (EAS) AF: 0.00 AC: 0 AN: 3501

South Asian (SAS) AF: 0.00 AC: 0 AN: 2586

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6027

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53059

Other (OTH) AF: 0.00 AC: 0 AN: 1485

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.19	T
FATHMM_MKL	Uncertain	0.80	D
M_CAP	Pathogenic	0.56	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-0.30	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.60
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.29
Sift	Benign	0.078	T
Sift4G	Benign	0.16	T
Polyphen		0.86	P
Vest4		0.42
MutPred		0.33		Loss of MoRF binding (P = 0.0067)
MVP		0.70
MPC		0.69
ClinPred		0.81	D
GERP RS		2.7
PromoterAI		-0.077	Neutral
Varity_R		0.16
gMVP		0.44
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs1395804892; hg19: chrX-79277821;