12-114394808-G-GT

Position:

• chr12-114394808-G-GT

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_181486.4(TBX5):​c.595_596insA​(p.Thr199AsnfsTer10) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TBX5 NM_181486.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.02

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-114394808-G-GT is Pathogenic according to our data. Variant chr12-114394808-G-GT is described in ClinVar as [Pathogenic]. Clinvar id is 543962.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.595_596insA	p.Thr199AsnfsTer10	frameshift_variant	6/9	ENST00000405440.7	NP_852259.1
TBX5	NM_000192.3	c.595_596insA	p.Thr199AsnfsTer10	frameshift_variant	6/9		NP_000183.2
TBX5	NM_080717.4	c.445_446insA	p.Thr149AsnfsTer10	frameshift_variant	5/8		NP_542448.1
TBX5	XM_017019912.2	c.643_644insA	p.Thr215AsnfsTer10	frameshift_variant	6/9		XP_016875401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBX5	ENST00000405440.7	c.595_596insA	p.Thr199AsnfsTer10	frameshift_variant	6/9	1	NM_181486.4	ENSP00000384152	P1
TBX5	ENST00000310346.8	c.595_596insA	p.Thr199AsnfsTer10	frameshift_variant	6/9	1		ENSP00000309913	P1
TBX5	ENST00000349716.9	c.445_446insA	p.Thr149AsnfsTer10	frameshift_variant	5/8	1		ENSP00000337723
TBX5	ENST00000526441.1	c.595_596insA	p.Thr199AsnfsTer10	frameshift_variant	5/7	1		ENSP00000433292

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Aortic valve disease 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2018

This sequence change creates a premature translational stop signal (p.Thr199Asnfs*10) in the TBX5 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with TBX5-related disease. Loss-of-function variants in TBX5 are known to be pathogenic (PMID: 16183809, 16917909). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

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: rs1555226005; hg19: chr12-114832613;