X-80022417-A-T

Variant summary

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

The NM_001109878.2(TBX22):c.148A>T(p.Ser50Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000923 in 1,083,713 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. 15/20 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)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: TBX22 NM_001109878.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.564

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=0.04328212).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX22	NM_001109878.2	c.148A>T	p.Ser50Cys	missense_variant	2/9	ENST00000373296.8
TBX22	NM_016954.2	c.148A>T	p.Ser50Cys	missense_variant	1/8
TBX22	NM_001109879.2	c.-209A>T		5_prime_UTR_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX22	ENST00000373296.8	c.148A>T	p.Ser50Cys	missense_variant	2/9	5	NM_001109878.2	P1
TBX22	ENST00000373294.8	c.148A>T	p.Ser50Cys	missense_variant	1/8	1		P1
TBX22	ENST00000476373.1	n.269A>T		non_coding_transcript_exon_variant	2/2	3
TBX22	ENST00000626498.2	c.148A>T	p.Ser50Cys	missense_variant, NMD_transcript_variant	2/9	2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.23e-7 AC: 1 AN: 1083713 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 352705

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: 0.00000120

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 13, 2019

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	0.045
Dann	Benign	0.50
DEOGEN2	Benign	0.040	T;T
FATHMM_MKL	Benign	0.048	N
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.043	T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.0	L;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.33	N;N
REVEL	Benign	0.16
Sift	Benign	0.17	T;T
Sift4G	Benign	0.11	T;T
Polyphen		0.0	B;B
Vest4		0.11
MutPred		0.31		Loss of phosphorylation at S50 (P = 2e-04);Loss of phosphorylation at S50 (P = 2e-04);
MVP		0.10
MPC		0.15
ClinPred		0.061	T
GERP RS		-9.2
Varity_R		0.063
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-79277916;