rs104894945

Variant names:

• chrX-80022435-G-A
• rs104894945
• NM_001109878.2:c.166G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-80022435-G-A
• chrX-80022435-G-C
• chrX-80022435-G-T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_016954.2(TBX22):​c.166G>A​(p.Glu56Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000561 in 1,070,105 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E56Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000056 (0 hom. 2 hem.)
• Consequence: TBX22 NM_016954.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.382
• 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: Labcorp Genetics (formerly Invitae), Orphanet, G2P
• Abruzzo-Erickson syndrome

  Inheritance: XL Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, G2P

ENSG00000300464 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.055299222).
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016954.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX22	NM_001109878.2	MANE Select	c.166G>A	p.Glu56Lys	missense	Exon 2 of 9	NP_001103348.1
	TBX22	NM_016954.2		c.166G>A	p.Glu56Lys	missense	Exon 1 of 8	NP_058650.1
	TBX22	NM_001109879.2		c.-191G>A		5_prime_UTR	Exon 2 of 9	NP_001103349.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX22	ENST00000373296.8	TSL:5 MANE Select	c.166G>A	p.Glu56Lys	missense	Exon 2 of 9	ENSP00000362393.3
	TBX22	ENST00000373294.8	TSL:1	c.166G>A	p.Glu56Lys	missense	Exon 1 of 8	ENSP00000362390.5
	TBX22	ENST00000924637.1		c.166G>A	p.Glu56Lys	missense	Exon 1 of 8	ENSP00000594696.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000561 AC: 6 AN: 1070105 Hom.: 0 Cov.: 31 AF XY: 0.00000576 AC XY: 2 AN XY: 347239

African (AFR) AF: 0.00 AC: 0 AN: 25499

American (AMR) AF: 0.00 AC: 0 AN: 30766

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18884

East Asian (EAS) AF: 0.0000352 AC: 1 AN: 28371

South Asian (SAS) AF: 0.00 AC: 0 AN: 50999

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38695

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3607

European-Non Finnish (NFE) AF: 0.00000483 AC: 4 AN: 828244

Other (OTH) AF: 0.0000222 AC: 1 AN: 45040

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	1.1
DANN	Benign	0.95
DEOGEN2	Benign	0.060	T
FATHMM_MKL	Benign	0.082	N
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.055	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.89	L
PhyloP100		-0.38
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.16
Sift	Benign	0.16	T
Sift4G	Benign	0.62	T
Polyphen		0.0070	B
Vest4		0.15
MutPred		0.25		Gain of MoRF binding (P = 0.0101)
MVP		0.21
MPC		0.17
ClinPred		0.038	T
GERP RS		0.72
PromoterAI		-0.069	Neutral
Varity_R		0.056
gMVP		0.26
Mutation Taster		=95/5	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: rs104894945; hg19: chrX-79277934; COSMIC: COSV100960949; COSMIC: COSV100960949;