chr16-30086355-CCT-C

Position:

• chr16-30086355-CCT-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_004608.4(TBX6):​c.1179_1180delAG​(p.Gly395fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,436,914 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TBX6 NM_004608.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.709

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 8 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 0.101 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-30086355-CCT-C is Pathogenic according to our data. Variant chr16-30086355-CCT-C is described in ClinVar as [Pathogenic]. Clinvar id is 252362.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.1179_1180delAG	p.Gly395fs	frameshift_variant	9/9	ENST00000395224.7	NP_004599.2
TBX6	XM_011545926.4	c.1179_1180delAG	p.Gly395fs	frameshift_variant	9/9		XP_011544228.1
TBX6	XM_047434551.1	c.1179_1180delAG	p.Gly395fs	frameshift_variant	8/8		XP_047290507.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBX6	ENST00000395224.7	c.1179_1180delAG	p.Gly395fs	frameshift_variant	9/9	1	NM_004608.4	ENSP00000378650.2
TBX6	ENST00000279386.6	c.1179_1180delAG	p.Gly395fs	frameshift_variant	8/8	1		ENSP00000279386.2
TBX6	ENST00000567664.5	n.*313_*314delAG		non_coding_transcript_exon_variant	7/7	5		ENSP00000460425.1
TBX6	ENST00000567664.5	n.*313_*314delAG		3_prime_UTR_variant	7/7	5		ENSP00000460425.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1436914 Hom.: 0 AF XY: 0.00000140 AC XY: 1 AN XY: 715122

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000120

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.05e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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. 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)		0.0		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: rs879253857; hg19: chr16-30097676;