12-114385476-C-G

Variant names:

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

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>C​(p.Ser252Thr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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:2
• 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-G is Pathogenic according to our data. Variant chr12-114385476-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 265264.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>C	p.Ser252Thr	missense_variant, splice_region_variant	Exon 7 of 9	ENST00000405440.7	NP_852259.1
TBX5	NM_000192.3	c.755G>C	p.Ser252Thr	missense_variant, splice_region_variant	Exon 7 of 9		NP_000183.2
TBX5	NM_080717.4	c.605G>C	p.Ser202Thr	missense_variant, splice_region_variant	Exon 6 of 8		NP_542448.1
TBX5	XM_017019912.2	c.803G>C	p.Ser268Thr	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>C	p.Ser252Thr	missense_variant, splice_region_variant	Exon 7 of 9	1	NM_181486.4	ENSP00000384152.3
TBX5	ENST00000310346.8	c.755G>C	p.Ser252Thr	missense_variant, splice_region_variant	Exon 7 of 9	1		ENSP00000309913.4
TBX5	ENST00000349716.9	c.605G>C	p.Ser202Thr	missense_variant, splice_region_variant	Exon 6 of 8	1		ENSP00000337723.5
TBX5	ENST00000526441.1	c.755G>C	p.Ser252Thr	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:2

Revision: criteria provided, single submitter

Submissions by phenotype

Holt-Oram syndrome Pathogenic:1

Jun 14, 2018

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:1

Dec 08, 2015

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The S252T missense variant has not been previously reported as disease causing nor as a benign polymorphism. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. S252T alters the last base of exon 7, immediately 5' of the canonical GT" splice donor site. In silico analysis with several different splice algorithms predicts that this splice donor site is abolished or altered, potentially leading to aberrant gene splicing. In addition, two other nucleotide changes (G>T aka S252I and G>A aka S252N) at this highly conserved position have been seen in multiple patients referred for clinical testing for HOS at GeneDx. Although the effect of these variants on gene splicing has not yet been demonstrated, S252I has been reported in the literature in association with Holt-Oram syndrome (Cross et al., 2000). In summary, we consider S252T to be likely pathogenic; however, the possibility that it is benign cannot be excluded." -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Uncertain	0.075	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	.;T;T;.
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;.;D;D
M_CAP	Uncertain	0.093	D
MetaRNN	Uncertain	0.56	D;D;D;D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Uncertain	2.2	.;M;M;M
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.90	N;N;N;N
REVEL	Uncertain	0.43
Sift	Benign	0.050	D;D;D;T
Sift4G	Benign	0.17	T;T;T;T
Polyphen		0.92, 0.85	.;P;P;P
Vest4		0.62
MutPred		0.28		.;Gain of catalytic residue at M247 (P = 0.1083);Gain of catalytic residue at M247 (P = 0.1083);Gain of catalytic residue at M247 (P = 0.1083);
MVP		0.74
MPC		1.4
ClinPred		0.95	D
GERP RS		5.3
Varity_R		0.28
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.95		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;