Genetic Variant TBX22:c.459-5T>A (chrX-80025598-T-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 4P and 12B. PS3BP4_StrongBS1BS2

The NM_001109878.2(TBX22):c.459-5T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000297 in 1,204,932 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 115 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 Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000589509: A functional study showed the c.459-5T>A variant almost abolished the wild type splicing product and led to a significant increase in the most upstream cryptic splice site product of exon 4 (Pauws et al., 2013).".

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., 7 hem., cov: 22)

Exomes 𝑓: 0.00031 ( 0 hom. 108 hem. )

Consequence

TBX22
NM_001109878.2 splice_region, intron

Scores

Splicing: ADA: 0.4644

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1B:1

Conservation

PhyloP100: 1.80

Publications

2 publications found

Variant links:

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

TBX22 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000589509: A functional study showed the c.459-5T>A variant almost abolished the wild type splicing product and led to a significant increase in the most upstream cryptic splice site product of exon 4 (Pauws et al., 2013).

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000188 (21/111699) while in subpopulation NFE AF = 0.00032 (17/53154). AF 95% confidence interval is 0.000203. There are 0 homozygotes in GnomAd4. There are 7 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 7 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TBX22	NM_001109878.2	MANE Select	c.459-5T>A	splice_region intron	N/A	NP_001103348.1	Q9Y458-1
TBX22	NM_016954.2		c.459-5T>A	splice_region intron	N/A	NP_058650.1	Q9Y458-1
TBX22	NM_001109879.2		c.99-5T>A	splice_region intron	N/A	NP_001103349.1	Q9Y458-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TBX22	ENST00000373296.8	TSL:5 MANE Select	c.459-5T>A	splice_region intron	N/A	ENSP00000362393.3	Q9Y458-1
TBX22	ENST00000373294.8	TSL:1	c.459-5T>A	splice_region intron	N/A	ENSP00000362390.5	Q9Y458-1
TBX22	ENST00000626877.1	TSL:1	n.338-5T>A	splice_region intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.000188

AC:

AN:

111699

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000326

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000947

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:

0.000320

Gnomad OTH

AF:

0.00136

GnomAD2 exomes

AF:

0.000203

AC:

AN:

182657

AF XY:

0.000282

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000369

Gnomad OTH exome

AF:

0.000885

GnomAD4 exome

AF:

0.000308

AC:

337

AN:

1093233

Hom.:

Cov.:

AF XY:

0.000301

AC XY:

108

AN XY:

358781

show subpopulations

African (AFR)

AF:

0.000608

AC:

AN:

26310

American (AMR)

AF:

0.00

AC:

AN:

35201

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19355

East Asian (EAS)

AF:

0.00

AC:

AN:

30185

South Asian (SAS)

AF:

0.000111

AC:

AN:

54052

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40497

Middle Eastern (MID)

AF:

0.00534

AC:

AN:

4118

European-Non Finnish (NFE)

AF:

0.000315

AC:

264

AN:

837607

Other (OTH)

AF:

0.000632

AC:

AN:

45908

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000188

AC:

AN:

111699

Hom.:

Cov.:

AF XY:

0.000207

AC XY:

AN XY:

33857

show subpopulations

African (AFR)

AF:

0.0000326

AC:

AN:

30684

American (AMR)

AF:

0.0000947

AC:

AN:

10565

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2655

East Asian (EAS)

AF:

0.00

AC:

AN:

3545

South Asian (SAS)

AF:

0.00

AC:

AN:

2635

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6062

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.000320

AC:

AN:

53154

Other (OTH)

AF:

0.00136

AC:

AN:

1476

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000651

Hom.:

Bravo

AF:

0.000155

EpiCase

AF:

0.000818

EpiControl

AF:

0.000711

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Abruzzo-Erickson syndrome (1)

Cleft palate with or without ankyloglossia, X-linked (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

(source)

DANN

Benign

0.68

PhyloP100

1.8

Mutation Taster

=97/3

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.46

dbscSNV1_RF

Benign

0.42

SpliceAI score (max)

0.37

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.37

Position offset: 5

DS_DG_spliceai

0.30

Position offset: 4

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over