X-80022439-C-T

Variant names:

• chrX-80022439-C-T
• rs770084170
• NM_001109878.2:c.170C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001109879.2(TBX22):​c.-187C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000468 in 1,068,850 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000047 (0 hom. 3 hem.)
• Consequence: TBX22 NM_001109879.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.438
• Publications: 1 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04216045).
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.00000468 (5/1068850) while in subpopulation AMR AF = 0.000163 (5/30603). AF 95% confidence interval is 0.0000639. There are 0 homozygotes in GnomAdExome4. There are 3 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Hemizygotes in GnomAdExome4 at 3 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001109879.2. 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.170C>T	p.Pro57Leu	missense	Exon 2 of 9	NP_001103348.1	Q9Y458-1
	TBX22	NM_001109879.2		c.-187C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 9	NP_001103349.1	Q9Y458-2
	TBX22	NM_016954.2		c.170C>T	p.Pro57Leu	missense	Exon 1 of 8	NP_058650.1	Q9Y458-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX22	ENST00000373296.8	TSL:5 MANE Select	c.170C>T	p.Pro57Leu	missense	Exon 2 of 9	ENSP00000362393.3	Q9Y458-1
	TBX22	ENST00000373294.8	TSL:1	c.170C>T	p.Pro57Leu	missense	Exon 1 of 8	ENSP00000362390.5	Q9Y458-1
	TBX22	ENST00000924637.1		c.170C>T	p.Pro57Leu	missense	Exon 1 of 8	ENSP00000594696.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.0000150 AC: 2 AN: 133145 AF XY: 0.0000237

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000919

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000468 AC: 5 AN: 1068850 Hom.: 0 Cov.: 30 AF XY: 0.00000865 AC XY: 3 AN XY: 346862

African (AFR) AF: 0.00 AC: 0 AN: 25462

American (AMR) AF: 0.000163 AC: 5 AN: 30603

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18869

East Asian (EAS) AF: 0.00 AC: 0 AN: 28265

South Asian (SAS) AF: 0.00 AC: 0 AN: 50910

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38665

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3561

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 827499

Other (OTH) AF: 0.00 AC: 0 AN: 45016

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	0.067
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	1.5
DANN	Benign	0.80
DEOGEN2	Benign	0.069	T
FATHMM_MKL	Benign	0.033	N
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.042	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.90	L
PhyloP100		-0.44
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.090
Sift	Benign	0.25	T
Sift4G	Benign	0.30	T
Polyphen		0.0	B
Vest4		0.079
MutPred		0.23		Loss of glycosylation at P57 (P = 0.0339)
MVP		0.12
MPC		0.16
ClinPred		0.021	T
GERP RS		-3.6
PromoterAI		0.023	Neutral
Varity_R		0.046
gMVP		0.35
Mutation Taster		=100/0	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: rs770084170; hg19: chrX-79277938;