rs587777683

Variant names:

• chr6-32048638-G-A
• rs587777683
• NM_001365276.2:c.9770C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP5

The NM_001428335.1(TNXB):​c.10511C>T​(p.Thr3504Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000525 in 1,334,512 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000052 (0 hom.)
• Consequence: TNXB NM_001428335.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 2.25
• Publications: 4 publications found

Genes affected

TNXB (HGNC:11976): (tenascin XB) This gene encodes a member of the tenascin family of extracellular matrix glycoproteins. The tenascins have anti-adhesive effects, as opposed to fibronectin which is adhesive. This protein is thought to function in matrix maturation during wound healing, and its deficiency has been associated with the connective tissue disorder Ehlers-Danlos syndrome. This gene localizes to the major histocompatibility complex (MHC) class III region on chromosome 6. It is one of four genes in this cluster which have been duplicated. The duplicated copy of this gene is incomplete and is a pseudogene which is transcribed but does not encode a protein. The structure of this gene is unusual in that it overlaps the CREBL1 and CYP21A2 genes at its 5' and 3' ends, respectively. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

TNXB Gene-Disease associations (from GenCC):

• Ehlers-Danlos syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• Ehlers-Danlos syndrome due to tenascin-X deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Illumina, PanelApp Australia, Orphanet
• familial vesicoureteral reflux

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• vesicoureteral reflux 8

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP5: Variant 6-32048638-G-A is Pathogenic according to our data. Variant chr6-32048638-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 144113.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001428335.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNXB	NM_001365276.2	MANE Select	c.9770C>T	p.Thr3257Ile	missense	Exon 29 of 44	NP_001352205.1
	TNXB	NM_001428335.1		c.10511C>T	p.Thr3504Ile	missense	Exon 30 of 45	NP_001415264.1
	TNXB	NM_019105.8		c.9764C>T	p.Thr3255Ile	missense	Exon 29 of 44	NP_061978.6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNXB	ENST00000644971.2	MANE Select	c.9770C>T	p.Thr3257Ile	missense	Exon 29 of 44	ENSP00000496448.1
	TNXB	ENST00000647633.1		c.10511C>T	p.Thr3504Ile	missense	Exon 30 of 45	ENSP00000497649.1
	TNXB	ENST00000375244.7	TSL:5	c.9770C>T	p.Thr3257Ile	missense	Exon 29 of 44	ENSP00000364393.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000168 AC: 3 AN: 178724 AF XY: 0.0000307

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000361

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000525 AC: 7 AN: 1334512 Hom.: 0 Cov.: 32 AF XY: 0.00000766 AC XY: 5 AN XY: 652650

African (AFR) AF: 0.00 AC: 0 AN: 30360

American (AMR) AF: 0.00 AC: 0 AN: 32428

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20176

East Asian (EAS) AF: 0.00 AC: 0 AN: 37858

South Asian (SAS) AF: 0.00 AC: 0 AN: 64244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45156

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4910

European-Non Finnish (NFE) AF: 0.00000670 AC: 7 AN: 1044720

Other (OTH) AF: 0.00 AC: 0 AN: 54660

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000837 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	-	-	Vesicoureteral reflux 8 (2)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.076	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.19	T
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-1.1	T
PhyloP100		2.2
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.62
Sift	Benign	0.13	T
Sift4G	Pathogenic	0.0010	D
Vest4		0.69
MVP		0.17
ClinPred		0.44	T
GERP RS		3.1
Varity_R		0.17
Mutation Taster		=31/69	disease causing

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: rs587777683; hg19: chr6-32016415;