rs773568096

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_181486.4(TBX5):c.1208G>C(p.Ser403Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,380 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. S403N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

TBX5
NM_181486.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.08

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

TBX5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10930756).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX5	NM_181486.4 link	c.1208G>C	p.Ser403Thr	missense_variant	Exon 9 of 9	ENST00000405440.7	NP_852259.1	Q99593-1
TBX5	NM_000192.3 link	c.1208G>C	p.Ser403Thr	missense_variant	Exon 9 of 9		NP_000183.2	Q99593-1
TBX5	NM_080717.4 link	c.1058G>C	p.Ser353Thr	missense_variant	Exon 8 of 8		NP_542448.1	Q99593-3
TBX5	XM_017019912.2 link	c.1256G>C	p.Ser419Thr	missense_variant	Exon 9 of 9		XP_016875401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TBX5	ENST00000405440.7 link	c.1208G>C	p.Ser403Thr	missense_variant	Exon 9 of 9	1	NM_181486.4	ENSP00000384152.3	Q99593-1
TBX5	ENST00000310346.8 link	c.1208G>C	p.Ser403Thr	missense_variant	Exon 9 of 9	1		ENSP00000309913.4	Q99593-1
TBX5	ENST00000349716.9 link	c.1058G>C	p.Ser353Thr	missense_variant	Exon 8 of 8	1		ENSP00000337723.5	Q99593-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000399

AC:

AN:

250876

AF XY:

0.00000737

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461380

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727026

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52910

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.29

.;T;T

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.20

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.69

T;.;T

M_CAP

Benign

0.0058

MetaRNN

Benign

0.11

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.81

.;L;L

PhyloP100

2.1

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.66

N;N;N

REVEL

Benign

0.046

Sift

Benign

0.079

T;T;T

Sift4G

Benign

0.52

T;T;T

Polyphen

0.079

.;B;B

Vest4

0.076

MutPred

0.28

.;Gain of catalytic residue at M404 (P = 0);Gain of catalytic residue at M404 (P = 0);

MVP

0.40

MPC

0.12

ClinPred

0.10

GERP RS

2.2

Varity_R

0.15

gMVP

0.30

Mutation Taster

=93/7

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over