12-114355868-G-C

Variant names:

• chr12-114355868-G-C
• rs1555223259
• NM_181486.4:c.1221C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_181486.4(TBX5):​c.1221C>G​(p.Tyr407*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TBX5 NM_181486.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.06

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.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.216 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-114355868-G-C is Pathogenic according to our data. Variant chr12-114355868-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 495227.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.1221C>G	p.Tyr407*	stop_gained	Exon 9 of 9	ENST00000405440.7	NP_852259.1
TBX5	NM_000192.3	c.1221C>G	p.Tyr407*	stop_gained	Exon 9 of 9		NP_000183.2
TBX5	NM_080717.4	c.1071C>G	p.Tyr357*	stop_gained	Exon 8 of 8		NP_542448.1
TBX5	XM_017019912.2	c.1269C>G	p.Tyr423*	stop_gained	Exon 9 of 9		XP_016875401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBX5	ENST00000405440.7	c.1221C>G	p.Tyr407*	stop_gained	Exon 9 of 9	1	NM_181486.4	ENSP00000384152.3
TBX5	ENST00000310346.8	c.1221C>G	p.Tyr407*	stop_gained	Exon 9 of 9	1		ENSP00000309913.4
TBX5	ENST00000349716.9	c.1071C>G	p.Tyr357*	stop_gained	Exon 8 of 8	1		ENSP00000337723.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ventricular septal defect;C0026266:Mitral regurgitation;C0344724:Atrial septal defect, ostium secundum type Pathogenic:1

Sep 08, 2017

Embryology Laboratory, Victor Chang Cardiac Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

This variant was identified in an Australian family of Caucasian origin. This novel truncating variant (with respect to ExAC) segregates with disease in 6 affected individuals across 3 generations. These patients all exhibit congenital heart disease, predominantly in the form of cardiac septal defects but also with electrical conduction anomalies of the heart. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.94	D
Vest4		0.86
GERP RS		2.4

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

LitVar

Other links and lift over

dbSNP: rs1555223259; hg19: chr12-114793673;