chrX-80022261-C-G

Variant names:

• chrX-80022261-C-G
• rs185298778
• ENST00000373294.8:c.-9C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001109878.2(TBX22):​c.-2-7C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000867 in 1,208,653 control chromosomes in the GnomAD database, including 6 homozygotes. There are 283 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0043 (2 hom., 120 hem., cov: 22)
  • Exomes 𝑓: 0.00052 (4 hom. 163 hem.)
• Consequence: TBX22 NM_001109878.2 splice_region, intron
• Scores: Splicing: ADA: 0.00003026
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0620
• Publications: 1 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant X-80022261-C-G is Benign according to our data. Variant chrX-80022261-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 804041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0043 (476/110797) while in subpopulation AFR AF = 0.015 (457/30430). AF 95% confidence interval is 0.0139. There are 2 homozygotes in GnomAd4. There are 120 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.-2-7C>G		splice_region intron	N/A	NP_001103348.1	Q9Y458-1
	TBX22	NM_016954.2		c.-9C>G		5_prime_UTR	Exon 1 of 8	NP_058650.1	Q9Y458-1
	TBX22	NM_001109879.2		c.-358-7C>G		splice_region intron	N/A	NP_001103349.1	Q9Y458-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX22	ENST00000373294.8	TSL:1	c.-9C>G		5_prime_UTR	Exon 1 of 8	ENSP00000362390.5	Q9Y458-1
	TBX22	ENST00000373296.8	TSL:5 MANE Select	c.-2-7C>G		splice_region intron	N/A	ENSP00000362393.3	Q9Y458-1
	TBX22	ENST00000924637.1		c.-9C>G		5_prime_UTR	Exon 1 of 8	ENSP00000594696.1

Frequencies

GnomAD3 genomes AF: 0.00429 AC: 475 AN: 110749 Hom.: 2 Cov.: 22

Gnomad AFR AF: 0.0150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000567

Gnomad OTH AF: 0.00203

GnomAD2 exomes AF: 0.00142 AC: 260 AN: 182524 AF XY: 0.00106

Gnomad AFR exome AF: 0.0178

Gnomad AMR exome AF: 0.000767

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.000665

GnomAD4 exome AF: 0.000521 AC: 572 AN: 1097856 Hom.: 4 Cov.: 31 AF XY: 0.000449 AC XY: 163 AN XY: 363222

African (AFR) AF: 0.0173 AC: 457 AN: 26395

American (AMR) AF: 0.000767 AC: 27 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19381

East Asian (EAS) AF: 0.00 AC: 0 AN: 30192

South Asian (SAS) AF: 0.000129 AC: 7 AN: 54119

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40522

Middle Eastern (MID) AF: 0.000725 AC: 3 AN: 4136

European-Non Finnish (NFE) AF: 0.0000154 AC: 13 AN: 841825

Other (OTH) AF: 0.00141 AC: 65 AN: 46081

GnomAD4 genome AF: 0.00430 AC: 476 AN: 110797 Hom.: 2 Cov.: 22 AF XY: 0.00363 AC XY: 120 AN XY: 33035

African (AFR) AF: 0.0150 AC: 457 AN: 30430

American (AMR) AF: 0.00124 AC: 13 AN: 10473

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2628

East Asian (EAS) AF: 0.00 AC: 0 AN: 3503

South Asian (SAS) AF: 0.00 AC: 0 AN: 2494

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6002

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.0000567 AC: 3 AN: 52869

Other (OTH) AF: 0.00200 AC: 3 AN: 1498

Alfa AF: 0.000305 Hom.: 1

Bravo AF: 0.00531

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Cleft palate with or without ankyloglossia, X-linked (1)
-	-	1	not provided (1)
-	-	1	TBX22-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	9.4
DANN	Benign	0.43
PhyloP100		0.062
PromoterAI		-0.0014	Neutral
Mutation Taster		=299/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000030
dbscSNV1_RF	Benign	0.012
SpliceAI score (max)		0.37		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.31		Position offset: -33
DS_AL_spliceai		0.37		Position offset: 7

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

Other links and lift over

dbSNP: rs185298778; hg19: chrX-79277760; COSMIC: COSV104681225;