X-80014862-G-A

Variant names:

• chrX-80014862-G-A
• rs746947861
• NM_001109878.2:c.-28G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001109878.2(TBX22):​c.-28G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000937 in 112,067 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 23 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00094 (0 hom., 23 hem., cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: TBX22 NM_001109878.2 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.351
• 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant X-80014862-G-A is Benign according to our data. Variant chrX-80014862-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 368661.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000937 (105/112067) while in subpopulation NFE AF = 0.00156 (83/53200). AF 95% confidence interval is 0.00129. There are 0 homozygotes in GnomAd4. There are 23 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 23 XL gene

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.-28G>A		5_prime_UTR	Exon 1 of 9	NP_001103348.1	Q9Y458-1
	TBX22	NM_001109879.2		c.-384G>A		5_prime_UTR	Exon 1 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.-28G>A		5_prime_UTR	Exon 1 of 9	ENSP00000362393.3	Q9Y458-1
	TBX22	ENST00000476373.1	TSL:3	n.94G>A		non_coding_transcript_exon	Exon 1 of 2
	TBX22	ENST00000626498.2	TSL:2	n.-28G>A		non_coding_transcript_exon	Exon 1 of 9	ENSP00000487527.1	A0A0D9SGI2

Frequencies

GnomAD3 genomes AF: 0.000937 AC: 105 AN: 112067 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000259

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000473

Gnomad ASJ AF: 0.00189

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00156

Gnomad OTH AF: 0.00266

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 140 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 74

African (AFR) AF: 0.00 AC: 0 AN: 6

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AF: 0.00 AC: 0 AN: 4

South Asian (SAS) AF: 0.00 AC: 0 AN: 2

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 113

Other (OTH) AF: 0.00 AC: 0 AN: 8

GnomAD4 genome AF: 0.000937 AC: 105 AN: 112067 Hom.: 0 Cov.: 23 AF XY: 0.000672 AC XY: 23 AN XY: 34207

African (AFR) AF: 0.000259 AC: 8 AN: 30845

American (AMR) AF: 0.000473 AC: 5 AN: 10577

Ashkenazi Jewish (ASJ) AF: 0.00189 AC: 5 AN: 2646

East Asian (EAS) AF: 0.00 AC: 0 AN: 3542

South Asian (SAS) AF: 0.00 AC: 0 AN: 2709

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6126

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.00156 AC: 83 AN: 53200

Other (OTH) AF: 0.00266 AC: 4 AN: 1503

Alfa AF: 0.00130 Hom.: 6

Bravo AF: 0.000865

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Cleft palate with or without ankyloglossia, X-linked (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.2
DANN	Benign	0.44
PhyloP100		0.35
PromoterAI		0.00010	Neutral
Mutation Taster		=300/0	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: rs746947861; hg19: chrX-79270361;