rs12196385

Variant names:

• chr6-32058203-G-A
• rs12196385
• NM_001365276.2:c.7680C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001365276.2(TNXB):​c.7680C>T​(p.Asp2560Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0884 in 1,612,278 control chromosomes in the GnomAD database, including 7,211 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (912 hom., cov: 31)
  • Exomes 𝑓: 0.087 (6299 hom.)
• Consequence: TNXB NM_001365276.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -7.03
• Publications: 12 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 6-32058203-G-A is Benign according to our data. Variant chr6-32058203-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261163.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-7.03 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.151 is higher than 0.05.

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.7680C>T	p.Asp2560Asp	synonymous	Exon 22 of 44	NP_001352205.1	P22105-3
	TNXB	NM_001428335.1		c.8421C>T	p.Asp2807Asp	synonymous	Exon 23 of 45	NP_001415264.1	A0A3B3ISX9
	TNXB	NM_019105.8		c.7680C>T	p.Asp2560Asp	synonymous	Exon 22 of 44	NP_061978.6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNXB	ENST00000644971.2	MANE Select	c.7680C>T	p.Asp2560Asp	synonymous	Exon 22 of 44	ENSP00000496448.1	P22105-3
	TNXB	ENST00000647633.1		c.8421C>T	p.Asp2807Asp	synonymous	Exon 23 of 45	ENSP00000497649.1	A0A3B3ISX9
	TNXB	ENST00000375244.7	TSL:5	c.7680C>T	p.Asp2560Asp	synonymous	Exon 22 of 44	ENSP00000364393.3	P22105-3

Frequencies

GnomAD3 genomes AF: 0.101 AC: 15366 AN: 151950 Hom.: 917 Cov.: 31

Gnomad AFR AF: 0.154

Gnomad AMI AF: 0.174

Gnomad AMR AF: 0.0528

Gnomad ASJ AF: 0.0957

Gnomad EAS AF: 0.0354

Gnomad SAS AF: 0.151

Gnomad FIN AF: 0.0538

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0881

Gnomad OTH AF: 0.0955

GnomAD2 exomes AF: 0.0818 AC: 20203 AN: 247096 AF XY: 0.0851

Gnomad AFR exome AF: 0.162

Gnomad AMR exome AF: 0.0454

Gnomad ASJ exome AF: 0.103

Gnomad EAS exome AF: 0.0335

Gnomad FIN exome AF: 0.0529

Gnomad NFE exome AF: 0.0810

Gnomad OTH exome AF: 0.0808

GnomAD4 exome AF: 0.0870 AC: 127073 AN: 1460210 Hom.: 6299 Cov.: 67 AF XY: 0.0879 AC XY: 63838 AN XY: 726408

African (AFR) AF: 0.162 AC: 5426 AN: 33470

American (AMR) AF: 0.0483 AC: 2161 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.104 AC: 2713 AN: 26136

East Asian (EAS) AF: 0.0211 AC: 836 AN: 39700

South Asian (SAS) AF: 0.129 AC: 11144 AN: 86244

European-Finnish (FIN) AF: 0.0532 AC: 2788 AN: 52430

Middle Eastern (MID) AF: 0.0810 AC: 434 AN: 5358

European-Non Finnish (NFE) AF: 0.0862 AC: 95882 AN: 1111838

Other (OTH) AF: 0.0943 AC: 5689 AN: 60318

GnomAD4 genome AF: 0.101 AC: 15378 AN: 152068 Hom.: 912 Cov.: 31 AF XY: 0.0996 AC XY: 7404 AN XY: 74348

African (AFR) AF: 0.154 AC: 6398 AN: 41436

American (AMR) AF: 0.0526 AC: 804 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0957 AC: 332 AN: 3470

East Asian (EAS) AF: 0.0356 AC: 184 AN: 5162

South Asian (SAS) AF: 0.150 AC: 721 AN: 4802

European-Finnish (FIN) AF: 0.0538 AC: 570 AN: 10590

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0881 AC: 5988 AN: 67992

Other (OTH) AF: 0.0945 AC: 200 AN: 2116

Alfa AF: 0.0957 Hom.: 335

Bravo AF: 0.104

Asia WGS AF: 0.0730 AC: 254 AN: 3478

EpiCase AF: 0.0947

EpiControl AF: 0.0874

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.32
DANN	Benign	0.68
PhyloP100		-7.0
Mutation Taster		=100/0	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: rs12196385; hg19: chr6-32025980; COSMIC: COSV64472979;