12-114385476-C-A

Variant names:

• chr12-114385476-C-A
• rs863223776
• NM_181486.4:c.755G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TBX5 NM_181486.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P: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
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 12-114385476-C-A is Pathogenic according to our data. Variant chr12-114385476-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 411099.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX5	NM_181486.4	c.755G>T	p.Ser252Ile	missense_variant, splice_region_variant	Exon 7 of 9	ENST00000405440.7	NP_852259.1
TBX5	NM_000192.3	c.755G>T	p.Ser252Ile	missense_variant, splice_region_variant	Exon 7 of 9		NP_000183.2
TBX5	NM_080717.4	c.605G>T	p.Ser202Ile	missense_variant, splice_region_variant	Exon 6 of 8		NP_542448.1
TBX5	XM_017019912.2	c.803G>T	p.Ser268Ile	missense_variant, splice_region_variant	Exon 7 of 9		XP_016875401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBX5	ENST00000405440.7	c.755G>T	p.Ser252Ile	missense_variant, splice_region_variant	Exon 7 of 9	1	NM_181486.4	ENSP00000384152.3
TBX5	ENST00000310346.8	c.755G>T	p.Ser252Ile	missense_variant, splice_region_variant	Exon 7 of 9	1		ENSP00000309913.4
TBX5	ENST00000349716.9	c.605G>T	p.Ser202Ile	missense_variant, splice_region_variant	Exon 6 of 8	1		ENSP00000337723.5
TBX5	ENST00000526441.1	c.755G>T	p.Ser252Ile	missense_variant, splice_region_variant	Exon 6 of 7	1		ENSP00000433292.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Aortic valve disease 2 Pathogenic:1

Feb 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 252 of the TBX5 protein (p.Ser252Ile). This variant also falls at the last nucleotide of exon 7, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Holt-Oram syndrome (PMID: 11183182; Invitae). ClinVar contains an entry for this variant (Variation ID: 411099). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects TBX5 function (PMID: 12499378, 26859351). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

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
DEOGEN2	Uncertain	0.46	.;T;T;.
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
MutationAssessor	Uncertain	2.2	.;M;M;M
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;