12-114403793-TG-TGG

Variant names:

• chr12-114403793-T-TG
• rs1057516042
• NM_181486.4:c.105dupC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_181486.4(TBX5):​c.105dupC​(p.Ser36GlnfsTer25) variant causes a frameshift change involving the alteration of a non-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: 33)
• Consequence: TBX5 NM_181486.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.83
• Publications: 1 publications found

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]

TBX5 Gene-Disease associations (from GenCC):

• Holt-Oram syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics
• heart conduction disease

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 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 12-114403793-T-TG is Pathogenic according to our data. Variant chr12-114403793-T-TG is described in ClinVar as Pathogenic. ClinVar VariationId is 870089.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.105dupC	p.Ser36GlnfsTer25	frameshift_variant	Exon 2 of 9	ENST00000405440.7	NP_852259.1
TBX5	NM_000192.3	c.105dupC	p.Ser36GlnfsTer25	frameshift_variant	Exon 2 of 9		NP_000183.2
TBX5	XM_017019912.2	c.153dupC	p.Ser52GlnfsTer25	frameshift_variant	Exon 2 of 9		XP_016875401.1
TBX5	NM_080717.4	c.-3-1874dupC		intron_variant	Intron 1 of 7		NP_542448.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBX5	ENST00000405440.7	c.105dupC	p.Ser36GlnfsTer25	frameshift_variant	Exon 2 of 9	1	NM_181486.4	ENSP00000384152.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Holt-Oram syndrome Pathogenic:1

Feb 09, 2018

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

TBX5 Ser36Thrfs*25 has not been previously reported and is absent in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). We identified this variant in a patient with Holt-Oram Syndrome, the patient initially presented with findings of left ventricular non-compaction and also has brachydactyly and pectus deformity associated to the condition (Ross et al., 2018). TBX5 variants have only ever been associated to Holt-Oram syndrome furthermore, TBX5 loss of function variants are an established mechanism of disease and the variant is very rare in the general population, consequently we classify TBX5 Ser36Thrfs*25 as 'pathogenic'. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.8
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1057516042; hg19: chr12-114841598;