17-61456593-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001321120.2(TBX4):​c.103G>T​(p.Ala35Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000982 in 1,527,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. A35V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000087 ( 0 hom. )

Consequence

TBX4
NM_001321120.2 missense

Scores

2
1
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.20
Variant links:
Genes affected
TBX4 (HGNC:11603): (T-box transcription factor 4) 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 gene is the human homolog of mouse Tbx4, which is closely linked to Tbx2 on mouse chromosome 11. Similarly this gene, like TBX2, maps to human chromosome 17. Expression studies in mouse and chicken show that Tbx4 is expressed in developing hindlimb, but not in forelimb buds, suggesting a role for this gene in regulating limb development and specification of limb identity. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.027040005).
BS2
High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TBX4NM_001321120.2 linkc.103G>T p.Ala35Ser missense_variant 2/9 ENST00000644296.1 NP_001308049.1 P57082-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TBX4ENST00000644296.1 linkc.103G>T p.Ala35Ser missense_variant 2/9 NM_001321120.2 ENSP00000495986.1 P57082-2
TBX4ENST00000240335.1 linkc.103G>T p.Ala35Ser missense_variant 1/81 ENSP00000240335.1 P57082-1
TBX4ENST00000642491.1 linkc.103G>T p.Ala35Ser missense_variant 1/8 ENSP00000495714.1 P57082-2
TBX4ENST00000589003.5 linkc.-125-31G>T intron_variant 3 ENSP00000467588.1 K7EPY2

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
151994
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000872
AC:
12
AN:
1375820
Hom.:
0
Cov.:
32
AF XY:
0.00000737
AC XY:
5
AN XY:
678282
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000112
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
151994
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74234
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000151
ExAC
AF:
0.0000246
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 11, 2024The c.103G>T (p.A35S) alteration is located in exon 1 (coding exon 1) of the TBX4 gene. This alteration results from a G to T substitution at nucleotide position 103, causing the alanine (A) at amino acid position 35 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.092
BayesDel_addAF
Benign
-0.11
T
BayesDel_noAF
Benign
-0.39
CADD
Benign
18
DANN
Benign
0.96
DEOGEN2
Benign
0.071
.;.;T;.
Eigen
Benign
-0.57
Eigen_PC
Benign
-0.43
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Benign
0.28
.;.;T;T
M_CAP
Pathogenic
0.57
D
MetaRNN
Benign
0.027
T;T;T;T
MetaSVM
Benign
-0.65
T
MutationAssessor
Benign
0.34
N;N;N;N
PrimateAI
Pathogenic
0.81
D
PROVEAN
Benign
0.010
N;.;N;.
REVEL
Benign
0.14
Sift
Benign
0.17
T;.;T;.
Sift4G
Benign
0.73
T;.;T;.
Polyphen
0.0060
.;.;B;.
Vest4
0.062
MutPred
0.23
Gain of glycosylation at A35 (P = 0.0043);Gain of glycosylation at A35 (P = 0.0043);Gain of glycosylation at A35 (P = 0.0043);Gain of glycosylation at A35 (P = 0.0043);
MVP
0.69
MPC
0.37
ClinPred
0.047
T
GERP RS
3.4
Varity_R
0.092
gMVP
0.26

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: rs765299000; hg19: chr17-59533954; API