chr6-32096752-G-T

Variant names:

• chr6-32096752-G-T
• rs9380279
• NM_001365276.2:c.1101C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001365276.2(TNXB):​c.1101C>A​(p.Asp367Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. D367D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TNXB NM_001365276.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.06
• Publications: 6 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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4012943).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365276.2. 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
	TNXB	NM_001365276.2	MANE Select	c.1101C>A	p.Asp367Glu	missense	Exon 3 of 44	NP_001352205.1
	TNXB	NM_001428335.1		c.1101C>A	p.Asp367Glu	missense	Exon 3 of 45	NP_001415264.1
	TNXB	NM_019105.8		c.1101C>A	p.Asp367Glu	missense	Exon 3 of 44	NP_061978.6

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNXB	ENST00000644971.2	MANE Select	c.1101C>A	p.Asp367Glu	missense	Exon 3 of 44	ENSP00000496448.1
	TNXB	ENST00000479795.1	TSL:1	c.1101C>A	p.Asp367Glu	missense	Exon 3 of 5	ENSP00000418248.1
	TNXB	ENST00000486148.1	TSL:1	n.1496C>A		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1404146 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 693682

African (AFR) AF: 0.00 AC: 0 AN: 31880

American (AMR) AF: 0.00 AC: 0 AN: 36506

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25236

East Asian (EAS) AF: 0.00 AC: 0 AN: 36184

South Asian (SAS) AF: 0.00 AC: 0 AN: 79754

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46688

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5626

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1083952

Other (OTH) AF: 0.00 AC: 0 AN: 58320

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-1.1	T
PhyloP100		4.1
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.13
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.0030	D
Vest4		0.28
MutPred		0.51		Gain of glycosylation at S369 (P = 0.1274)
MVP		0.28
ClinPred		0.98	D
GERP RS		3.9
Varity_R		0.30
Mutation Taster		=83/17	polymorphism

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: rs9380279; hg19: chr6-32064529;