rs927204453

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate

The NM_005996.4(TBX3):​c.370G>T​(p.Val124Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

TBX3
NM_005996.4 missense

Scores

14
4
1

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 5.85
Variant links:
Genes affected
TBX3 (HGNC:11602): (T-box transcription factor 3) 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. This protein is a transcriptional repressor and is thought to play a role in the anterior/posterior axis of the tetrapod forelimb. Mutations in this gene cause ulnar-mammary syndrome, affecting limb, apocrine gland, tooth, hair, and genital development. Alternative splicing of this gene results in three transcript variants encoding different isoforms; however, the full length nature of one variant has not been determined. [provided by RefSeq, Jul 2008]
TBX3-AS1 (HGNC:55471): (TBX3 antisense RNA 1)

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1
In a DNA_binding_region T-box; first part (size 113) in uniprot entity TBX3_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_005996.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.947
PP5
Variant 12-114682831-C-A is Pathogenic according to our data. Variant chr12-114682831-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 522089.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TBX3NM_005996.4 linkuse as main transcriptc.370G>T p.Val124Phe missense_variant 1/7 ENST00000349155.7
TBX3NM_016569.4 linkuse as main transcriptc.370G>T p.Val124Phe missense_variant 1/8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TBX3ENST00000349155.7 linkuse as main transcriptc.370G>T p.Val124Phe missense_variant 1/71 NM_005996.4 P4O15119-2
TBX3ENST00000257566.7 linkuse as main transcriptc.370G>T p.Val124Phe missense_variant 1/81 A1O15119-1
TBX3-AS1ENST00000660721.1 linkuse as main transcriptn.343+197C>A intron_variant, non_coding_transcript_variant
TBX3ENST00000552054.1 linkuse as main transcriptn.604G>T non_coding_transcript_exon_variant 1/22

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsNov 06, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.46
D
BayesDel_noAF
Pathogenic
0.43
CADD
Pathogenic
33
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.90
.;D
Eigen
Pathogenic
0.87
Eigen_PC
Pathogenic
0.81
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.96
D;D
M_CAP
Uncertain
0.27
D
MetaRNN
Pathogenic
0.95
D;D
MetaSVM
Pathogenic
0.93
D
MutationAssessor
Pathogenic
2.9
M;M
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.87
D
PROVEAN
Pathogenic
-4.8
D;D
REVEL
Pathogenic
0.88
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0010
D;D
Polyphen
1.0
D;D
Vest4
0.91
MutPred
0.81
Gain of catalytic residue at V124 (P = 0.0643);Gain of catalytic residue at V124 (P = 0.0643);
MVP
0.94
MPC
2.4
ClinPred
1.0
D
GERP RS
5.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.98
gMVP
0.93

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs927204453; hg19: chr12-115120636; API