X-80022439-C-T

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04216045).
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome 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 gnomad4_exome. There are 3 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Hemizygotes in GnomAdExome4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX22	NM_001109878.2	c.170C>T	p.Pro57Leu	missense_variant	Exon 2 of 9	ENST00000373296.8	NP_001103348.1
TBX22	NM_001109879.2	c.-187C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 9		NP_001103349.1
TBX22	NM_016954.2	c.170C>T	p.Pro57Leu	missense_variant	Exon 1 of 8		NP_058650.1
TBX22	NM_001109879.2	c.-187C>T		5_prime_UTR_variant	Exon 2 of 9		NP_001103349.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBX22	ENST00000373296.8	c.170C>T	p.Pro57Leu	missense_variant	Exon 2 of 9	5	NM_001109878.2	ENSP00000362393.3
TBX22	ENST00000373294.8	c.170C>T	p.Pro57Leu	missense_variant	Exon 1 of 8	1		ENSP00000362390.5
TBX22	ENST00000476373.1	n.291C>T		non_coding_transcript_exon_variant	Exon 2 of 2	3
TBX22	ENST00000626498.2	n.170C>T		non_coding_transcript_exon_variant	Exon 2 of 9	2		ENSP00000487527.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.0000150 AC: 2 AN: 133145 Hom.: 0 AF XY: 0.0000237 AC XY: 1 AN XY: 42147

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 SAS 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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000163

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: 0.00

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

Inborn genetic diseases Uncertain:1

Feb 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.170C>T (p.P57L) alteration is located in exon 2 (coding exon 1) of the TBX22 gene. This alteration results from a C to T substitution at nucleotide position 170, causing the proline (P) at amino acid position 57 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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;T
FATHMM_MKL	Benign	0.033	N
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.042	T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.90	L;L
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.090
Sift	Benign	0.25	T;T
Sift4G	Benign	0.30	T;T
Polyphen		0.0	B;B
Vest4		0.079
MutPred		0.23		Loss of glycosylation at P57 (P = 0.0339);Loss of glycosylation at P57 (P = 0.0339);
MVP		0.12
MPC		0.16
ClinPred		0.021	T
GERP RS		-3.6
Varity_R		0.046
gMVP		0.35

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: rs770084170; hg19: chrX-79277938;