12-114355868-G-C

Position:

• chr12-114355868-G-C

Variant summary

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

The ENST00000405440.7(TBX5):​c.1221C>G​(p.Tyr407Ter) 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 ENST00000405440.7 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 2 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/exons	MANE	Protein	UniProt
TBX5	NM_181486.4	c.1221C>G	p.Tyr407Ter	stop_gained	9/9	ENST00000405440.7	NP_852259.1
TBX5	NM_000192.3	c.1221C>G	p.Tyr407Ter	stop_gained	9/9		NP_000183.2
TBX5	NM_080717.4	c.1071C>G	p.Tyr357Ter	stop_gained	8/8		NP_542448.1
TBX5	XM_017019912.2	c.1269C>G	p.Tyr423Ter	stop_gained	9/9		XP_016875401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBX5	ENST00000405440.7	c.1221C>G	p.Tyr407Ter	stop_gained	9/9	1	NM_181486.4	ENSP00000384152	P1
TBX5	ENST00000310346.8	c.1221C>G	p.Tyr407Ter	stop_gained	9/9	1		ENSP00000309913	P1
TBX5	ENST00000349716.9	c.1071C>G	p.Tyr357Ter	stop_gained	8/8	1		ENSP00000337723

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

Pathogenic, criteria provided, single submitter

research

Embryology Laboratory, Victor Chang Cardiac Research Institute

Sep 08, 2017

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
MutationTaster	Benign	1.0	D;D;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;