rs1555225989

chr12-114394771-A-AAACG

Variant summary

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

The NM_181486.4(TBX5):c.632_633insCGTT(p.Ile212ValfsTer18) 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: 9.32

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 12-114394771-A-AAACG is Pathogenic according to our data. Variant chr12-114394771-A-AAACG is described in ClinVar as [Pathogenic]. Clinvar id is 477658.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX5	NM_181486.4	c.632_633insCGTT	p.Ile212ValfsTer18	frameshift_variant	6/9	ENST00000405440.7
TBX5	NM_000192.3	c.632_633insCGTT	p.Ile212ValfsTer18	frameshift_variant	6/9
TBX5	NM_080717.4	c.482_483insCGTT	p.Ile162ValfsTer18	frameshift_variant	5/8
TBX5	XM_017019912.2	c.680_681insCGTT	p.Ile228ValfsTer18	frameshift_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX5	ENST00000405440.7	c.632_633insCGTT	p.Ile212ValfsTer18	frameshift_variant	6/9	1	NM_181486.4	P1
TBX5	ENST00000310346.8	c.632_633insCGTT	p.Ile212ValfsTer18	frameshift_variant	6/9	1		P1
TBX5	ENST00000349716.9	c.482_483insCGTT	p.Ile162ValfsTer18	frameshift_variant	5/8	1
TBX5	ENST00000526441.1	c.632_633insCGTT	p.Ile212ValfsTer18	frameshift_variant	5/7	1

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

Invitae

Mar 11, 2017

While this particular variant has not been reported in the literature, loss-of-function variants in TBX5 are known to be pathogenic (PMID: 16917909, 16183809). This sequence change inserts 4 nucleotides in exon 6 of the TBX5 mRNA (c.629_632dupCGTT), causing a frameshift at codon 212. This creates a premature translational stop signal (p.Ile212Valfs*18) 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

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555225989; hg19: chr12-114832576;