rs529527925

Variant names:

• chr6-32048363-C-A
• rs529527925
• NM_001365276.2:c.10045G>T

Your query was ambiguous. Multiple possible variants found:

• chr6-32048363-C-A
• chr6-32048363-C-G
• chr6-32048363-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001428335.1(TNXB):​c.10786G>T​(p.Ala3596Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000378 in 1,322,560 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/21 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A3596P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000038 (0 hom.)
• Consequence: TNXB NM_001428335.1 missense, splice_region
• Scores: Splicing: ADA: 0.8829
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.330
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07977235).

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.10045G>T	p.Ala3349Ser	missense splice_region	Exon 29 of 44	NP_001352205.1
	TNXB	NM_001428335.1		c.10786G>T	p.Ala3596Ser	missense splice_region	Exon 30 of 45	NP_001415264.1
	TNXB	NM_019105.8		c.10039G>T	p.Ala3347Ser	missense splice_region	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.10045G>T	p.Ala3349Ser	missense splice_region	Exon 29 of 44	ENSP00000496448.1
	TNXB	ENST00000647633.1		c.10786G>T	p.Ala3596Ser	missense splice_region	Exon 30 of 45	ENSP00000497649.1
	TNXB	ENST00000375244.7	TSL:5	c.10045G>T	p.Ala3349Ser	missense splice_region	Exon 29 of 44	ENSP00000364393.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000378 AC: 5 AN: 1322560 Hom.: 0 Cov.: 32 AF XY: 0.00000466 AC XY: 3 AN XY: 643782

African (AFR) AF: 0.00 AC: 0 AN: 29770

American (AMR) AF: 0.00 AC: 0 AN: 28214

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19068

East Asian (EAS) AF: 0.00 AC: 0 AN: 37946

South Asian (SAS) AF: 0.00 AC: 0 AN: 61028

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45088

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5194

European-Non Finnish (NFE) AF: 0.00000480 AC: 5 AN: 1041912

Other (OTH) AF: 0.00 AC: 0 AN: 54340

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	2.8
DANN	Benign	0.92
DEOGEN2	Benign	0.019	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.081	N
LIST_S2	Benign	0.087	T
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.080	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.33
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.044
Sift	Benign	0.078	T
Sift4G	Benign	0.36	T
Vest4		0.076
MVP		0.082
ClinPred		0.14	T
GERP RS		-1.8
Varity_R		0.069
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.88
dbscSNV1_RF	Benign	0.65
SpliceAI score (max)		0.030		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: rs529527925; hg19: chr6-32016140; COSMIC: COSV64476009; COSMIC: COSV64476009;