NM_181486.4:c.781A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_181486.4(TBX5):​c.781A>G​(p.Ser261Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. S261C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

TBX5
NM_181486.4 missense

Scores

5
9
5

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.67

Publications

4 publications found
Variant links:
Genes affected
TBX5 (HGNC:11604): (T-box transcription factor 5) 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 closely linked to related family member T-box 3 (ulnar mammary syndrome) on human chromosome 12. The encoded protein may play a role in heart development and specification of limb identity. Mutations in this gene have been associated with Holt-Oram syndrome, a developmental disorder affecting the heart and upper limbs. Several transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2008]
TBX5 Gene-Disease associations (from GenCC):
  • Holt-Oram syndrome
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics
  • heart conduction disease
    Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.77

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TBX5NM_181486.4 linkc.781A>G p.Ser261Gly missense_variant Exon 8 of 9 ENST00000405440.7 NP_852259.1 Q99593-1
TBX5NM_000192.3 linkc.781A>G p.Ser261Gly missense_variant Exon 8 of 9 NP_000183.2 Q99593-1
TBX5NM_080717.4 linkc.631A>G p.Ser211Gly missense_variant Exon 7 of 8 NP_542448.1 Q99593-3
TBX5XM_017019912.2 linkc.829A>G p.Ser277Gly missense_variant Exon 8 of 9 XP_016875401.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TBX5ENST00000405440.7 linkc.781A>G p.Ser261Gly missense_variant Exon 8 of 9 1 NM_181486.4 ENSP00000384152.3 Q99593-1
TBX5ENST00000310346.8 linkc.781A>G p.Ser261Gly missense_variant Exon 8 of 9 1 ENSP00000309913.4 Q99593-1
TBX5ENST00000349716.9 linkc.631A>G p.Ser211Gly missense_variant Exon 7 of 8 1 ENSP00000337723.5 Q99593-3
TBX5ENST00000526441.1 linkc.781A>G p.Ser261Gly missense_variant Exon 7 of 7 1 ENSP00000433292.1 Q99593-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.00
AC:
0
AN:
251182
AF XY:
0.00
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1461880
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
727244
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26134
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53420
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5764
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1112006
Other (OTH)
AF:
0.00
AC:
0
AN:
60396
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.20
BayesDel_addAF
Pathogenic
0.21
D
BayesDel_noAF
Uncertain
0.060
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.38
.;T;T;.
Eigen
Pathogenic
0.71
Eigen_PC
Pathogenic
0.72
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.82
T;.;T;T
M_CAP
Uncertain
0.088
D
MetaRNN
Pathogenic
0.77
D;D;D;D
MetaSVM
Uncertain
0.23
D
MutationAssessor
Uncertain
2.3
.;M;M;M
PhyloP100
7.7
PrimateAI
Uncertain
0.74
T
PROVEAN
Benign
-1.6
N;N;N;N
REVEL
Uncertain
0.55
Sift
Uncertain
0.0030
D;D;D;D
Sift4G
Uncertain
0.048
D;D;D;D
Polyphen
1.0, 0.91
.;D;D;P
Vest4
0.73
MutPred
0.34
.;Loss of phosphorylation at S261 (P = 0.0182);Loss of phosphorylation at S261 (P = 0.0182);Loss of phosphorylation at S261 (P = 0.0182);
MVP
0.82
MPC
0.86
ClinPred
0.95
D
GERP RS
5.6
Varity_R
0.44
gMVP
0.49
Mutation Taster
=3/97
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.10
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs377625550; hg19: chr12-114804171; API