16-30088756-GC-GCC

Position:

• chr16-30088756-GC-GCC

Variant summary

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

The NM_004608.4(TBX6):​c.704dupG​(p.Met236fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,644 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: TBX6 NM_004608.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.578

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 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 16-30088756-G-GC is Pathogenic according to our data. Variant chr16-30088756-G-GC is described in ClinVar as [Pathogenic]. Clinvar id is 243053.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.704dupG	p.Met236fs	frameshift_variant	5/9	ENST00000395224.7	NP_004599.2
TBX6	XM_011545926.4	c.704dupG	p.Met236fs	frameshift_variant	5/9		XP_011544228.1
TBX6	XM_047434551.1	c.704dupG	p.Met236fs	frameshift_variant	4/8		XP_047290507.1
TBX6	XR_007064904.1	n.827dupG		non_coding_transcript_exon_variant	5/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBX6	ENST00000395224.7	c.704dupG	p.Met236fs	frameshift_variant	5/9	1	NM_004608.4	ENSP00000378650.2
TBX6	ENST00000279386.6	c.704dupG	p.Met236fs	frameshift_variant	4/8	1		ENSP00000279386.2
TBX6	ENST00000553607.1	c.704dupG	p.Met236fs	frameshift_variant	4/5	1		ENSP00000461223.1
TBX6	ENST00000567664.5	n.704dupG		non_coding_transcript_exon_variant	4/7	5		ENSP00000460425.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461644 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727102

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Spondylocostal dysostosis 5 Pathogenic:1

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). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs758051786; hg19: chr16-30100077;