16-30086227-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

The NM_004608.4(TBX6):c.1309T>C(p.Ter437ArgextTer81) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TBX6 NM_004608.4 stop_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.00

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-30086227-A-G is Pathogenic according to our data. Variant chr16-30086227-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3062294.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (BayesDel_addAF=-0.0433196).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBX6	NM_004608.4	c.1309T>C	p.Ter437ArgextTer81	stop_lost	9/9	ENST00000395224.7
TBX6	XM_011545926.4	c.1309T>C	p.Ter437ArgextTer81	stop_lost	9/9
TBX6	XM_047434551.1	c.1309T>C	p.Ter437ArgextTer81	stop_lost	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBX6	ENST00000395224.7	c.1309T>C	p.Ter437ArgextTer81	stop_lost	9/9	1	NM_004608.4	P1
TBX6	ENST00000279386.6	c.1309T>C	p.Ter437ArgextTer81	stop_lost	8/8	1		P1
TBX6	ENST00000567664.5	c.*443T>C		3_prime_UTR_variant, NMD_transcript_variant	7/7	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Spondylocostal dysostosis 5 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics Department, Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology

-

A previously undescribed nucleotide variant creates a p.Ter437ArgextTer81 in the TBX6 gene. The variant was observed in heterozygous state in an individual affected with multiple hemivertebra and short spine. Loss-of-function variants are reported in patients with Spondylocostal dysostosis 5, 122600. Another heterozygous variant causing stop-loss (c.1311A>T) was previously described in familial Spondylocostal dysostosis (OMIM: 122600, Spondylocostal dysostosis 5) [Sparrow et al., 2013, PMID: 23335591].The variant is not present in population database (gnomAD no frequency). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	16
Dann	Benign	0.82
Eigen	Pathogenic	0.79
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.82	D
MutationTaster	Benign	1.0	N;N
Vest4		0.25
GERP RS		4.7

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-30097548;