chr12-114366188-AT-A

Variant names:

• chr12-114366188-AT-A
• rs878853750
• NM_181486.4:c.958delA

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.958delA​(p.Ile320PhefsTer74) 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TBX5 NM_181486.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.50

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 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.385 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 12-114366188-AT-A is Pathogenic according to our data. Variant chr12-114366188-AT-A is described in ClinVar as [Pathogenic]. Clinvar id is 237218.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-114366188-AT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBX5	NM_181486.4	c.958delA	p.Ile320PhefsTer74	frameshift_variant	Exon 8 of 9	ENST00000405440.7	NP_852259.1
TBX5	NM_000192.3	c.958delA	p.Ile320PhefsTer74	frameshift_variant	Exon 8 of 9		NP_000183.2
TBX5	NM_080717.4	c.808delA	p.Ile270PhefsTer74	frameshift_variant	Exon 7 of 8		NP_542448.1
TBX5	XM_017019912.2	c.1006delA	p.Ile336PhefsTer74	frameshift_variant	Exon 8 of 9		XP_016875401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBX5	ENST00000405440.7	c.958delA	p.Ile320PhefsTer74	frameshift_variant	Exon 8 of 9	1	NM_181486.4	ENSP00000384152.3
TBX5	ENST00000310346.8	c.958delA	p.Ile320PhefsTer74	frameshift_variant	Exon 8 of 9	1		ENSP00000309913.4
TBX5	ENST00000349716.9	c.808delA	p.Ile270PhefsTer74	frameshift_variant	Exon 7 of 8	1		ENSP00000337723.5
TBX5	ENST00000526441.1	c.958delA	p.Ile320PhefsTer30	frameshift_variant	Exon 7 of 7	1		ENSP00000433292.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

Jan 27, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

While this particular variant has not been reported in the literature, truncating variants in TBX5 are known to be pathogenic (PMID: 16183809, 16917909). This sequence change deletes 1 nucleotide from exon 8 of the TBX5 mRNA (c.958delA), causing a frameshift at codon 320. This creates a premature translational stop signal (p.Ile320Phefs*74) and is expected to result in an absent or disrupted protein product. 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: rs878853750; hg19: chr12-114803993;