rs1555883805

chr17-61482947-GC-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_001321120.2(TBX4):c.1077del(p.Ser360LeufsTer20) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A358A) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TBX4 NM_001321120.2 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.80

Genes affected

TBX4 (HGNC:11603): (T-box transcription factor 4) 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 the human homolog of mouse Tbx4, which is closely linked to Tbx2 on mouse chromosome 11. Similarly this gene, like TBX2, maps to human chromosome 17. Expression studies in mouse and chicken show that Tbx4 is expressed in developing hindlimb, but not in forelimb buds, suggesting a role for this gene in regulating limb development and specification of limb identity. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 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. There are 6 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX4	NM_001321120.2	c.1077del	p.Ser360LeufsTer20	frameshift_variant	9/9	ENST00000644296.1
TBX4	NM_018488.3	c.1074del	p.Ser359LeufsTer20	frameshift_variant	8/8
TBX4	XM_011525490.3	c.1266del	p.Ser423LeufsTer20	frameshift_variant	9/9
TBX4	XM_011525491.3	c.1263del	p.Ser422LeufsTer20	frameshift_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX4	ENST00000644296.1	c.1077del	p.Ser360LeufsTer20	frameshift_variant	9/9		NM_001321120.2	A1
TBX4	ENST00000240335.1	c.1074del	p.Ser359LeufsTer20	frameshift_variant	8/8	1		P4
TBX4	ENST00000589449.5	n.836del		non_coding_transcript_exon_variant	7/8	1
TBX4	ENST00000642491.1	c.1077del	p.Ser360LeufsTer20	frameshift_variant	8/8			A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pulmonary arterial hypertension associated with congenital heart disease Uncertain:1

Uncertain significance, criteria provided, single submitter

case-control

Wendy Chung Laboratory, Columbia University Medical Center

Jun 27, 2018

The maternal DNA sample was negative for the variant. No paternal sample was available and thus, we are uncertain whether the origin of the allele is paternal or de novo. -

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: rs1555883805; hg19: chr17-59560308;