rs786204039

Positions:

• chr16-30086285-G-GA

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The ENST00000395224.7(TBX6):​c.1250_1251insT​(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 ENST00000395224.7 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.37

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]

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. 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 id is 188054.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBX6	NM_004608.4	c.1250_1251insT	p.Leu419SerfsTer68	frameshift_variant	9/9	ENST00000395224.7	NP_004599.2
TBX6	XM_011545926.4	c.1250_1251insT	p.Leu419SerfsTer68	frameshift_variant	9/9		XP_011544228.1
TBX6	XM_047434551.1	c.1250_1251insT	p.Leu419SerfsTer68	frameshift_variant	8/8		XP_047290507.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBX6	ENST00000395224.7	c.1250_1251insT	p.Leu419SerfsTer68	frameshift_variant	9/9	1	NM_004608.4	ENSP00000378650	P1
TBX6	ENST00000279386.6	c.1250_1251insT	p.Leu419SerfsTer68	frameshift_variant	8/8	1		ENSP00000279386	P1
TBX6	ENST00000567664.5	c.*384_*385insT		3_prime_UTR_variant, NMD_transcript_variant	7/7	5		ENSP00000460425

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

Pathogenic, criteria provided, single submitter	research	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	Nov 15, 2015	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). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 22, 2015	- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs786204039; hg19: chr16-30097606;