dbSNP rs147405081: TBX5:p.Val263Leu (chr12-114366360-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_181486.4(TBX5):c.787G>T(p.Val263Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. V263M) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TBX5
NM_181486.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.57

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX5	NM_181486.4 link	c.787G>T	p.Val263Leu	missense_variant	Exon 8 of 9	ENST00000405440.7	NP_852259.1	Q99593-1
TBX5	NM_000192.3 link	c.787G>T	p.Val263Leu	missense_variant	Exon 8 of 9		NP_000183.2	Q99593-1
TBX5	NM_080717.4 link	c.637G>T	p.Val213Leu	missense_variant	Exon 7 of 8		NP_542448.1	Q99593-3
TBX5	XM_017019912.2 link	c.835G>T	p.Val279Leu	missense_variant	Exon 8 of 9		XP_016875401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TBX5	ENST00000405440.7 link	c.787G>T	p.Val263Leu	missense_variant	Exon 8 of 9	1	NM_181486.4	ENSP00000384152.3	Q99593-1
TBX5	ENST00000310346.8 link	c.787G>T	p.Val263Leu	missense_variant	Exon 8 of 9	1		ENSP00000309913.4	Q99593-1
TBX5	ENST00000349716.9 link	c.637G>T	p.Val213Leu	missense_variant	Exon 7 of 8	1		ENSP00000337723.5	Q99593-3
TBX5	ENST00000526441.1 link	c.787G>T	p.Val263Leu	missense_variant	Exon 7 of 7	1		ENSP00000433292.1	Q99593-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727238

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

.;T;T;.

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

D;.;D;D

M_CAP

Benign

0.043

MetaRNN

Uncertain

0.49

T;T;T;T

MetaSVM

Benign

-0.37

MutationAssessor

Uncertain

2.1

.;M;M;M

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-0.73

N;N;N;N

REVEL

Uncertain

0.36

Sift

Benign

0.039

D;D;D;T

Sift4G

Benign

0.24

T;T;T;T

Polyphen

0.74, 0.59

.;P;P;P

Vest4

0.62

MutPred

0.43

.;Gain of catalytic residue at P259 (P = 0.0254);Gain of catalytic residue at P259 (P = 0.0254);Gain of catalytic residue at P259 (P = 0.0254);

MVP

0.82

MPC

1.0

ClinPred

0.92

GERP RS

5.6

Varity_R

0.14

gMVP

0.41

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over