rs863223776

chr12-114385476-C-Achr12-114385476-C-Gchr12-114385476-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_181486.4(TBX5):c.755G>T(p.Ser252Ile) variant causes a missense, splice region 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. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S252N) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TBX5 NM_181486.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.48

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-114385476-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 213819.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX5	NM_181486.4	c.755G>T	p.Ser252Ile	missense_variant, splice_region_variant	7/9	ENST00000405440.7
TBX5	NM_000192.3	c.755G>T	p.Ser252Ile	missense_variant, splice_region_variant	7/9
TBX5	NM_080717.4	c.605G>T	p.Ser202Ile	missense_variant, splice_region_variant	6/8
TBX5	XM_017019912.2	c.803G>T	p.Ser268Ile	missense_variant, splice_region_variant	7/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX5	ENST00000405440.7	c.755G>T	p.Ser252Ile	missense_variant, splice_region_variant	7/9	1	NM_181486.4	P1
TBX5	ENST00000310346.8	c.755G>T	p.Ser252Ile	missense_variant, splice_region_variant	7/9	1		P1
TBX5	ENST00000349716.9	c.605G>T	p.Ser202Ile	missense_variant, splice_region_variant	6/8	1
TBX5	ENST00000526441.1	c.755G>T	p.Ser252Ile	missense_variant, splice_region_variant	6/7	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Aortic valve disease 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 22, 2016

Algorithms developed to predict the effect of nucleotide changes on mRNA splicing suggest that this intronic variant may alter mRNA splicing, but this prediction has not been confirmed by published transcriptional studies. Experimental studies have reported conflicting data regarding the effect of this missense variant. No effect was reported on several aspects of protein function including: DNA binding, ANF pre-mRNA splicing, interaction with NKx2.5 and recruitment of TAZ (PMID: 19648116, 11555635, 16332960, 26859351). However, a deleterious effect was reported on the interaction with NKx2.5 (PMID: 12499378), while in another study, this variant was found to reduce interaction with the nucleosome remodeling and deacetylase repressor complex (NuRD) (PMID: 26859351).  The clinical significance of these findings is not fully understood. This sequence change has been reported in an individual affected with Holt-Oram syndrome (PMID: 11183182). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with isoleucine at codon 252 of the TBX5 protein (p.Ser252Ile). The serine residue is highly conserved and there is a large physicochemical difference between serine and isoleucine. It also falls at the last nucleotide of exon 7 of the TBX5 coding sequence. In summary, this sequence change has been reported in an affected individual, and has an unknown effect on splicing. However, there is some  conflicting data regarding the effect of this change on protein function. For these reasons it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
Cadd	Pathogenic	33
Dann	Uncertain	1.0
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;.;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.83	D;D;D;D
MetaSVM	Uncertain	0.35	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.7	N;N;N;N
REVEL	Pathogenic	0.73
Sift	Uncertain	0.010	D;D;D;D
Sift4G	Benign	0.062	T;D;D;T
Polyphen		0.33, 0.91	.;B;B;P
Vest4		0.81
MutPred		0.70		.;Loss of phosphorylation at S252 (P = 0.0182);Loss of phosphorylation at S252 (P = 0.0182);Loss of phosphorylation at S252 (P = 0.0182);
MVP		0.91
MPC		1.2
ClinPred		0.97	D
GERP RS		5.3
Varity_R		0.45
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.93		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs863223776; hg19: chr12-114823281;