chrX-80022324-C-T

Variant names:

• chrX-80022324-C-T
• rs1923747301
• NM_001109878.2:c.55C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001109878.2(TBX22):​c.55C>T​(p.Pro19Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,098,054 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P19H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: TBX22 NM_001109878.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.815
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03173524).

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.55C>T	p.Pro19Ser	missense	Exon 2 of 9	NP_001103348.1	Q9Y458-1
	TBX22	NM_016954.2		c.55C>T	p.Pro19Ser	missense	Exon 1 of 8	NP_058650.1	Q9Y458-1
	TBX22	NM_001109879.2		c.-302C>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.55C>T	p.Pro19Ser	missense	Exon 2 of 9	ENSP00000362393.3	Q9Y458-1
	TBX22	ENST00000373294.8	TSL:1	c.55C>T	p.Pro19Ser	missense	Exon 1 of 8	ENSP00000362390.5	Q9Y458-1
	TBX22	ENST00000924637.1		c.55C>T	p.Pro19Ser	missense	Exon 1 of 8	ENSP00000594696.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1098054 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 363416

African (AFR) AF: 0.00 AC: 0 AN: 26403

American (AMR) AF: 0.00 AC: 0 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19384

East Asian (EAS) AF: 0.00 AC: 0 AN: 30192

South Asian (SAS) AF: 0.00 AC: 0 AN: 54126

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40529

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841991

Other (OTH) AF: 0.00 AC: 0 AN: 46087

GnomAD4 genome Cov.: 22

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	0.098
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	0.43
DANN	Benign	0.79
DEOGEN2	Benign	0.049	T
FATHMM_MKL	Benign	0.087	N
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.032	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.58	N
PhyloP100		-0.81
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.20
Sift	Benign	0.50	T
Sift4G	Benign	0.68	T
Polyphen		0.0050	B
Vest4		0.14
MutPred		0.19		Gain of phosphorylation at P19 (P = 0.0126)
MVP		0.28
MPC		0.16
ClinPred		0.030	T
GERP RS		-2.6
PromoterAI		0.067	Neutral
Varity_R		0.037
gMVP		0.48
Mutation Taster		=94/6	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: rs1923747301; hg19: chrX-79277823;