NM_001109878.2:c.56C>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_ModerateBS1BS2

The NM_001109878.2(TBX22):c.56C>A(p.Pro19His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,209,284 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P19S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000012 ( 0 hom. 7 hem. )

Consequence

TBX22
NM_001109878.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.95

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:

ENSG00000300464 (HGNC:):

ENSG00000300464 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.16090599).

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000018 (2/111241) while in subpopulation EAS AF = 0.000573 (2/3491). AF 95% confidence interval is 0.000102. There are 0 homozygotes in GnomAd4. There are 0 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High Hemizygotes in GnomAdExome4 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	HGVSp	Effect	Exon Rank	Protein	UniProt
TBX22	NM_001109878.2	MANE Select	c.56C>A	p.Pro19His	missense	Exon 2 of 9	NP_001103348.1	Q9Y458-1
TBX22	NM_016954.2		c.56C>A	p.Pro19His	missense	Exon 1 of 8	NP_058650.1	Q9Y458-1
TBX22	NM_001109879.2		c.-301C>A		5_prime_UTR	Exon 2 of 9	NP_001103349.1	Q9Y458-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TBX22	ENST00000373296.8	TSL:5 MANE Select	c.56C>A	p.Pro19His	missense	Exon 2 of 9	ENSP00000362393.3	Q9Y458-1
TBX22	ENST00000373294.8	TSL:1	c.56C>A	p.Pro19His	missense	Exon 1 of 8	ENSP00000362390.5	Q9Y458-1
TBX22	ENST00000924637.1		c.56C>A	p.Pro19His	missense	Exon 1 of 8	ENSP00000594696.1

Frequencies

GnomAD3 genomes

AF:

0.0000180

AC:

AN:

111241

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000573

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000328

AC:

AN:

183038

AF XY:

0.0000296

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000434

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000118

AC:

AN:

1098043

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

363405

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26400

American (AMR)

AF:

0.00

AC:

AN:

35205

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19385

East Asian (EAS)

AF:

0.000397

AC:

AN:

30192

South Asian (SAS)

AF:

0.00

AC:

AN:

54126

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40526

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4135

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

841987

Other (OTH)

AF:

0.0000217

AC:

AN:

46087

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.433

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:

0.0000180

AC:

AN:

111241

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33469

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30541

American (AMR)

AF:

0.00

AC:

AN:

10509

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2640

East Asian (EAS)

AF:

0.000573

AC:

AN:

3491

South Asian (SAS)

AF:

0.00

AC:

AN:

2580

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6039

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53028

Other (OTH)

AF:

0.00

AC:

AN:

1492

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000412

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

FATHMM_MKL

Benign

0.41

M_CAP

Pathogenic

0.61

MetaRNN

Benign

0.16

MetaSVM

Benign

-0.34

MutationAssessor

Benign

1.9

PhyloP100

1.9

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.2

REVEL

Benign

0.25

Sift

Uncertain

0.018

Sift4G

Benign

0.072

Polyphen

0.97

Vest4

0.33

MutPred

0.21

Loss of glycosylation at P19 (P = 0.025)

MVP

0.52

MPC

0.56

ClinPred

0.22

GERP RS

2.6

PromoterAI

0.083

Neutral

(source)

Varity_R

0.26

gMVP

0.45

Mutation Taster

=98/2

polymorphism

(source)

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

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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