chr6-32052735-T-C

Variant names:

• chr6-32052735-T-C
• rs17207895
• NM_001365276.2:c.9050A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001365276.2(TNXB):​c.9050A>G​(p.Lys3017Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.02 in 1,613,740 control chromosomes in the GnomAD database, including 751 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (93 hom., cov: 32)
  • Exomes 𝑓: 0.020 (658 hom.)
• Consequence: TNXB NM_001365276.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.71
• Publications: 7 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: Orphanet, Labcorp Genetics (formerly Invitae), Illumina, Genomics England PanelApp, PanelApp Australia
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028343797).
• BP6: Variant 6-32052735-T-C is Benign according to our data. Variant chr6-32052735-T-C is described in ClinVar as Benign. ClinVar VariationId is 261173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0198 (3011/152226) while in subpopulation NFE AF = 0.0239 (1626/68008). AF 95% confidence interval is 0.0229. There are 93 homozygotes in GnomAd4. There are 1466 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 93 AR,AD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNXB	NM_001365276.2	MANE Select	c.9050A>G	p.Lys3017Arg	missense	Exon 26 of 44	NP_001352205.1	P22105-3
	TNXB	NM_001428335.1		c.9791A>G	p.Lys3264Arg	missense	Exon 27 of 45	NP_001415264.1	A0A3B3ISX9
	TNXB	NM_019105.8		c.9044A>G	p.Lys3015Arg	missense	Exon 26 of 44	NP_061978.6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNXB	ENST00000644971.2	MANE Select	c.9050A>G	p.Lys3017Arg	missense	Exon 26 of 44	ENSP00000496448.1	P22105-3
	TNXB	ENST00000647633.1		c.9791A>G	p.Lys3264Arg	missense	Exon 27 of 45	ENSP00000497649.1	A0A3B3ISX9
	TNXB	ENST00000375244.7	TSL:5	c.9050A>G	p.Lys3017Arg	missense	Exon 26 of 44	ENSP00000364393.3	P22105-3

Frequencies

GnomAD3 genomes AF: 0.0198 AC: 3012 AN: 152108 Hom.: 93 Cov.: 32

Gnomad AFR AF: 0.00275

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.0204

Gnomad ASJ AF: 0.175

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.00415

Gnomad FIN AF: 0.0221

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0239

Gnomad OTH AF: 0.0244

GnomAD2 exomes AF: 0.0239 AC: 5899 AN: 246360 AF XY: 0.0243

Gnomad AFR exome AF: 0.00163

Gnomad AMR exome AF: 0.0133

Gnomad ASJ exome AF: 0.163

Gnomad EAS exome AF: 0.00173

Gnomad FIN exome AF: 0.0207

Gnomad NFE exome AF: 0.0269

Gnomad OTH exome AF: 0.0308

GnomAD4 exome AF: 0.0200 AC: 29197 AN: 1461514 Hom.: 658 Cov.: 32 AF XY: 0.0205 AC XY: 14886 AN XY: 727048

African (AFR) AF: 0.00284 AC: 95 AN: 33480

American (AMR) AF: 0.0145 AC: 650 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.153 AC: 3988 AN: 26136

East Asian (EAS) AF: 0.00103 AC: 41 AN: 39700

South Asian (SAS) AF: 0.00435 AC: 375 AN: 86254

European-Finnish (FIN) AF: 0.0210 AC: 1115 AN: 53220

Middle Eastern (MID) AF: 0.0218 AC: 126 AN: 5768

European-Non Finnish (NFE) AF: 0.0192 AC: 21314 AN: 1111860

Other (OTH) AF: 0.0247 AC: 1493 AN: 60372

GnomAD4 genome AF: 0.0198 AC: 3011 AN: 152226 Hom.: 93 Cov.: 32 AF XY: 0.0197 AC XY: 1466 AN XY: 74418

African (AFR) AF: 0.00274 AC: 114 AN: 41538

American (AMR) AF: 0.0204 AC: 312 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.175 AC: 608 AN: 3468

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5160

South Asian (SAS) AF: 0.00415 AC: 20 AN: 4820

European-Finnish (FIN) AF: 0.0221 AC: 235 AN: 10620

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0239 AC: 1626 AN: 68008

Other (OTH) AF: 0.0241 AC: 51 AN: 2112

Alfa AF: 0.00657 Hom.: 71

Bravo AF: 0.0193

TwinsUK AF: 0.0173 AC: 64

ALSPAC AF: 0.0135 AC: 52

ESP6500AA AF: 0.00453 AC: 12

ESP6500EA AF: 0.0239 AC: 123

ExAC AF: 0.0224 AC: 2709

Asia WGS AF: 0.00260 AC: 10 AN: 3478

EpiCase AF: 0.0345

EpiControl AF: 0.0357

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.027	T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.7
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.14
Sift	Benign	0.26	T
Sift4G	Benign	0.19	T
Vest4		0.13
ClinPred		0.018	T
GERP RS		3.2
Varity_R		0.085
Mutation Taster		=98/2	polymorphism (auto)

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: rs17207895; hg19: chr6-32020512; COSMIC: COSV99056686;