chr16-30086285-G-GA

Variant names:

• chr16-30086285-G-GA
• rs786204039
• NM_004608.4:c.1250dupT

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_004608.4(TBX6):​c.1250dupT​(p.Leu419SerfsTer68) 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: TBX6 NM_004608.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.37
• Publications: 4 publications found

Genes affected

TBX6 (HGNC:11605): (T-box transcription factor 6) 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. Knockout studies in mice indicate that this gene is important for specification of paraxial mesoderm structures. [provided by RefSeq, Aug 2008]

TBX6 Gene-Disease associations (from GenCC):

• spondylocostal dysostosis 5

  Inheritance: Unknown, SD Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal dominant spondylocostal dysostosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital anomaly of kidney and urinary tract

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 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. Fraction of 0.0465 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-30086285-G-GA is Pathogenic according to our data. Variant chr16-30086285-G-GA is described in ClinVar as Pathogenic. ClinVar VariationId is 188054.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004608.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX6	NM_004608.4	MANE Select	c.1250dupT	p.Leu419SerfsTer68	frameshift	Exon 9 of 9	NP_004599.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBX6	ENST00000395224.7	TSL:1 MANE Select	c.1250dupT	p.Leu419SerfsTer68	frameshift	Exon 9 of 9	ENSP00000378650.2
	TBX6	ENST00000279386.6	TSL:1	c.1250dupT	p.Leu419SerfsTer68	frameshift	Exon 8 of 8	ENSP00000279386.2
	TBX6	ENST00000567664.5	TSL:5	n.*384dupT		non_coding_transcript_exon	Exon 7 of 7	ENSP00000460425.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Spondylocostal dysostosis 5 Pathogenic:2

Nov 15, 2015

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

This variant was observed in 1 individual with a vertebral malformation and rib abnormalities. The variant was found to be in trans with a high-risk TBX6 haplotype, T-C-A (rs2289292, rs3809624, rs3809627).

Jan 22, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.4
Mutation Taster		=4/196	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs786204039; hg19: chr16-30097606;