rs62402693

Variant names:

• chr6-32045210-A-G
• rs62402693
• NM_001365276.2:c.10723T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_001365276.2(TNXB):​c.10723T>C​(p.Ser3575Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.121 in 1,553,184 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (0 hom., cov: 24)
  • Exomes 𝑓: 0.12 (1 hom.)
• Consequence: TNXB NM_001365276.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.15
• Publications: 14 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: Illumina, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024795234).
• BP6: Variant 6-32045210-A-G is Benign according to our data. Variant chr6-32045210-A-G is described in ClinVar as Benign. ClinVar VariationId is 403558.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.10723T>C	p.Ser3575Pro	missense	Exon 32 of 44	NP_001352205.1	P22105-3
	TNXB	NM_001428335.1		c.11464T>C	p.Ser3822Pro	missense	Exon 33 of 45	NP_001415264.1	A0A3B3ISX9
	TNXB	NM_019105.8		c.10717T>C	p.Ser3573Pro	missense	Exon 32 of 44	NP_061978.6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNXB	ENST00000644971.2	MANE Select	c.10723T>C	p.Ser3575Pro	missense	Exon 32 of 44	ENSP00000496448.1	P22105-3
	TNXB	ENST00000451343.4	TSL:1	c.10T>C	p.Ser4Pro	missense	Exon 1 of 13	ENSP00000407685.1	P22105-2
	TNXB	ENST00000490077.5	TSL:1	n.550T>C		non_coding_transcript_exon	Exon 2 of 14

Frequencies

GnomAD3 genomes AF: 0.149 AC: 21454 AN: 144376 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.257

Gnomad AMI AF: 0.0256

Gnomad AMR AF: 0.145

Gnomad ASJ AF: 0.0891

Gnomad EAS AF: 0.0833

Gnomad SAS AF: 0.166

Gnomad FIN AF: 0.0554

Gnomad MID AF: 0.204

Gnomad NFE AF: 0.109

Gnomad OTH AF: 0.173

GnomAD2 exomes AF: 0.114 AC: 26206 AN: 230376 AF XY: 0.117

Gnomad AFR exome AF: 0.245

Gnomad AMR exome AF: 0.0943

Gnomad ASJ exome AF: 0.0811

Gnomad EAS exome AF: 0.0810

Gnomad FIN exome AF: 0.0569

Gnomad NFE exome AF: 0.102

Gnomad OTH exome AF: 0.125

GnomAD4 exome AF: 0.118 AC: 166189 AN: 1408718 Hom.: 1 Cov.: 33 AF XY: 0.119 AC XY: 83568 AN XY: 700502

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.266 AC: 8216 AN: 30916

American (AMR) AF: 0.103 AC: 4361 AN: 42402

Ashkenazi Jewish (ASJ) AF: 0.0877 AC: 2190 AN: 24978

East Asian (EAS) AF: 0.0814 AC: 3177 AN: 39050

South Asian (SAS) AF: 0.188 AC: 15337 AN: 81790

European-Finnish (FIN) AF: 0.0620 AC: 3213 AN: 51782

Middle Eastern (MID) AF: 0.153 AC: 796 AN: 5206

European-Non Finnish (NFE) AF: 0.113 AC: 121244 AN: 1074676

Other (OTH) AF: 0.132 AC: 7655 AN: 57918

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.149 AC: 21472 AN: 144466 Hom.: 0 Cov.: 24 AF XY: 0.147 AC XY: 10338 AN XY: 70560

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.257 AC: 9786 AN: 38042

American (AMR) AF: 0.145 AC: 2067 AN: 14286

Ashkenazi Jewish (ASJ) AF: 0.0891 AC: 293 AN: 3288

East Asian (EAS) AF: 0.0833 AC: 423 AN: 5076

South Asian (SAS) AF: 0.166 AC: 761 AN: 4588

European-Finnish (FIN) AF: 0.0554 AC: 580 AN: 10472

Middle Eastern (MID) AF: 0.192 AC: 51 AN: 266

European-Non Finnish (NFE) AF: 0.109 AC: 7155 AN: 65604

Other (OTH) AF: 0.171 AC: 333 AN: 1944

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.133 Hom.: 0

ExAC AF: 0.124 AC: 14552

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Uncertain	0.078	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.062
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-0.60	T
PhyloP100		1.2
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.0040	D
Vest4		0.28
MPC		4.1
ClinPred		0.031	T
GERP RS		2.3
Varity_R		0.70
gMVP		0.69
Mutation Taster		=90/10	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: rs62402693; hg19: chr6-32012987; COSMIC: COSV64472579; COSMIC: COSV64472579;