X-80022412-G-A

Position:

• chrX-80022412-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001109878.2(TBX22):​c.143G>A​(p.Arg48Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: TBX22 NM_001109878.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.119

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.054014683).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBX22	NM_001109878.2	c.143G>A	p.Arg48Lys	missense_variant	2/9	ENST00000373296.8	NP_001103348.1
TBX22	NM_016954.2	c.143G>A	p.Arg48Lys	missense_variant	1/8		NP_058650.1
TBX22	NM_001109879.2	c.-214G>A		5_prime_UTR_variant	2/9		NP_001103349.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBX22	ENST00000373296.8	c.143G>A	p.Arg48Lys	missense_variant	2/9	5	NM_001109878.2	ENSP00000362393	P1
TBX22	ENST00000373294.8	c.143G>A	p.Arg48Lys	missense_variant	1/8	1		ENSP00000362390	P1
TBX22	ENST00000476373.1	n.264G>A		non_coding_transcript_exon_variant	2/2	3
TBX22	ENST00000626498.2	c.143G>A	p.Arg48Lys	missense_variant, NMD_transcript_variant	2/9	2		ENSP00000487527

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cleft palate with or without ankyloglossia, X-linked Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	2.3
DANN	Benign	0.80
DEOGEN2	Benign	0.056	T;T
FATHMM_MKL	Benign	0.089	N
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.054	T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.1	L;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.040	N;N
REVEL	Benign	0.15
Sift	Benign	0.91	T;T
Sift4G	Benign	0.89	T;T
Polyphen		0.0010	B;B
Vest4		0.12
MutPred		0.32		Gain of ubiquitination at R48 (P = 0.0069);Gain of ubiquitination at R48 (P = 0.0069);
MVP		0.30
MPC		0.15
ClinPred		0.022	T
GERP RS		-0.59
Varity_R		0.061
gMVP		0.28

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: rs1923753821; hg19: chrX-79277911;