NM_004608.4:c.1311A>T

Variant names:

• chr16-30086225-T-A
• rs587777113
• NM_004608.4:c.1311A>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM4 PP5

The NM_004608.4(TBX6):​c.1311A>T​(p.Ter437Cysext*?) 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TBX6 NM_004608.4 stop_lost
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 2.65
• Publications: 3 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_004608.4 Downstream stopcodon found after 26 codons.
• PP5: Variant 16-30086225-T-A is Pathogenic according to our data. Variant chr16-30086225-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 100633.Status of the report is no_assertion_criteria_provided, 0 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.1311A>T	p.Ter437Cysext*?	stop_lost	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.1311A>T	p.Ter437Cysext*?	stop_lost	Exon 9 of 9	ENSP00000378650.2
	TBX6	ENST00000279386.6	TSL:1	c.1311A>T	p.Ter437Cysext*?	stop_lost	Exon 8 of 8	ENSP00000279386.2
	TBX6	ENST00000567664.5	TSL:5	n.*445A>T		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:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Spondylocostal dysostosis 5 Pathogenic:1

Apr 15, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Spondylocostal dysostosis 2, autosomal recessive Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	16
DANN	Benign	0.72
Eigen	Pathogenic	0.78
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.84	D
PhyloP100		2.6
Vest4		0.25
GERP RS		4.7
Mutation Taster		=21/179	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587777113; hg19: chr16-30097546;