X-80022341-C-T

Variant names:

• chrX-80022341-C-T
• rs138387312
• NM_001109878.2:c.72C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001109878.2(TBX22):​c.72C>T​(p.Leu24Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00176 in 1,209,470 control chromosomes in the GnomAD database, including 22 homozygotes. There are 545 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0080 (10 hom., 223 hem., cov: 22)
  • Exomes 𝑓: 0.0011 (12 hom. 322 hem.)
• Consequence: TBX22 NM_001109878.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.04
• Publications: 4 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant X-80022341-C-T is Benign according to our data. Variant chrX-80022341-C-T is described in ClinVar as Benign. ClinVar VariationId is 368664.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.04 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00803 (896/111597) while in subpopulation AFR AF = 0.0257 (787/30642). AF 95% confidence interval is 0.0242. There are 10 homozygotes in GnomAd4. There are 223 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 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.72C>T	p.Leu24Leu	synonymous	Exon 2 of 9	NP_001103348.1	Q9Y458-1
	TBX22	NM_016954.2		c.72C>T	p.Leu24Leu	synonymous	Exon 1 of 8	NP_058650.1	Q9Y458-1
	TBX22	NM_001109879.2		c.-285C>T		5_prime_UTR	Exon 2 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.72C>T	p.Leu24Leu	synonymous	Exon 2 of 9	ENSP00000362393.3	Q9Y458-1
	TBX22	ENST00000373294.8	TSL:1	c.72C>T	p.Leu24Leu	synonymous	Exon 1 of 8	ENSP00000362390.5	Q9Y458-1
	TBX22	ENST00000924637.1		c.72C>T	p.Leu24Leu	synonymous	Exon 1 of 8	ENSP00000594696.1

Frequencies

GnomAD3 genomes AF: 0.00792 AC: 883 AN: 111547 Hom.: 10 Cov.: 22

Gnomad AFR AF: 0.0255

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00540

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00770

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000753

Gnomad OTH AF: 0.0101

GnomAD2 exomes AF: 0.00297 AC: 543 AN: 182765 AF XY: 0.00202

Gnomad AFR exome AF: 0.0278

Gnomad AMR exome AF: 0.00157

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00847

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000368

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00112 AC: 1230 AN: 1097873 Hom.: 12 Cov.: 31 AF XY: 0.000886 AC XY: 322 AN XY: 363239

African (AFR) AF: 0.0291 AC: 767 AN: 26397

American (AMR) AF: 0.00176 AC: 62 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19382

East Asian (EAS) AF: 0.00543 AC: 164 AN: 30187

South Asian (SAS) AF: 0.000296 AC: 16 AN: 54101

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40525

Middle Eastern (MID) AF: 0.00193 AC: 8 AN: 4135

European-Non Finnish (NFE) AF: 0.0000368 AC: 31 AN: 841853

Other (OTH) AF: 0.00395 AC: 182 AN: 46088

GnomAD4 genome AF: 0.00803 AC: 896 AN: 111597 Hom.: 10 Cov.: 22 AF XY: 0.00659 AC XY: 223 AN XY: 33829

African (AFR) AF: 0.0257 AC: 787 AN: 30642

American (AMR) AF: 0.00539 AC: 57 AN: 10577

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2644

East Asian (EAS) AF: 0.00773 AC: 27 AN: 3495

South Asian (SAS) AF: 0.00 AC: 0 AN: 2613

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6097

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.0000753 AC: 4 AN: 53117

Other (OTH) AF: 0.0139 AC: 21 AN: 1510

Alfa AF: 0.0123 Hom.: 111

Bravo AF: 0.00936

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Cleft palate with or without ankyloglossia, X-linked (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.78
DANN	Benign	0.83
PhyloP100		-1.0
PromoterAI		-0.047	Neutral
Mutation Taster		=99/1	polymorphism (auto)

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: rs138387312; hg19: chrX-79277840;