rs204900

Variant names:

• chr6-32088803-A-C
• rs204900
• NM_001365276.2:c.2761T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001365276.2(TNXB):​c.2761T>G​(p.Ser921Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.114 in 1,575,098 control chromosomes in the GnomAD database, including 14,625 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2327 hom., cov: 32)
  • Exomes 𝑓: 0.11 (12298 hom.)
• Consequence: TNXB NM_001365276.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.46
• Publications: 20 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=0.003803134).
• BP6: Variant 6-32088803-A-C is Benign according to our data. Variant chr6-32088803-A-C is described in ClinVar as Benign. ClinVar VariationId is 261131.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.284 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.2761T>G	p.Ser921Ala	missense	Exon 6 of 44	NP_001352205.1	P22105-3
	TNXB	NM_001428335.1		c.2761T>G	p.Ser921Ala	missense	Exon 6 of 45	NP_001415264.1	A0A3B3ISX9
	TNXB	NM_019105.8		c.2761T>G	p.Ser921Ala	missense	Exon 6 of 44	NP_061978.6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNXB	ENST00000644971.2	MANE Select	c.2761T>G	p.Ser921Ala	missense	Exon 6 of 44	ENSP00000496448.1	P22105-3
	TNXB	ENST00000647633.1		c.2761T>G	p.Ser921Ala	missense	Exon 6 of 45	ENSP00000497649.1	A0A3B3ISX9
	TNXB	ENST00000375244.7	TSL:5	c.2761T>G	p.Ser921Ala	missense	Exon 6 of 44	ENSP00000364393.3	P22105-3

Frequencies

GnomAD3 genomes AF: 0.152 AC: 23139 AN: 152102 Hom.: 2314 Cov.: 32

Gnomad AFR AF: 0.261

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.150

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.107

Gnomad SAS AF: 0.297

Gnomad FIN AF: 0.0619

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.0963

Gnomad OTH AF: 0.189

GnomAD2 exomes AF: 0.136 AC: 26744 AN: 196842 AF XY: 0.148

Gnomad AFR exome AF: 0.253

Gnomad AMR exome AF: 0.0989

Gnomad ASJ exome AF: 0.103

Gnomad EAS exome AF: 0.102

Gnomad FIN exome AF: 0.0647

Gnomad NFE exome AF: 0.0955

Gnomad OTH exome AF: 0.134

GnomAD4 exome AF: 0.110 AC: 157160 AN: 1422878 Hom.: 12298 Cov.: 33 AF XY: 0.118 AC XY: 82787 AN XY: 704100

African (AFR) AF: 0.267 AC: 8739 AN: 32706

American (AMR) AF: 0.105 AC: 4136 AN: 39378

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 2755 AN: 25398

East Asian (EAS) AF: 0.109 AC: 4132 AN: 37998

South Asian (SAS) AF: 0.341 AC: 27354 AN: 80222

European-Finnish (FIN) AF: 0.0678 AC: 3343 AN: 49308

Middle Eastern (MID) AF: 0.271 AC: 1518 AN: 5596

European-Non Finnish (NFE) AF: 0.0895 AC: 97816 AN: 1093360

Other (OTH) AF: 0.125 AC: 7367 AN: 58912

GnomAD4 genome AF: 0.152 AC: 23177 AN: 152220 Hom.: 2327 Cov.: 32 AF XY: 0.155 AC XY: 11553 AN XY: 74420

African (AFR) AF: 0.261 AC: 10845 AN: 41530

American (AMR) AF: 0.149 AC: 2284 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 385 AN: 3472

East Asian (EAS) AF: 0.106 AC: 551 AN: 5180

South Asian (SAS) AF: 0.297 AC: 1433 AN: 4826

European-Finnish (FIN) AF: 0.0619 AC: 657 AN: 10612

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.0963 AC: 6547 AN: 67994

Other (OTH) AF: 0.186 AC: 392 AN: 2110

Alfa AF: 0.118 Hom.: 3532

Bravo AF: 0.159

TwinsUK AF: 0.0847 AC: 314

ALSPAC AF: 0.0955 AC: 368

ESP6500AA AF: 0.231 AC: 946

ESP6500EA AF: 0.0906 AC: 758

ExAC AF: 0.121 AC: 14343

Asia WGS AF: 0.249 AC: 866 AN: 3478

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	0.19
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.70
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-0.94	T
PhyloP100		1.5
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.056
Sift	Benign	0.061	T
Sift4G	Uncertain	0.051	T
Vest4		0.12
ClinPred		0.022	T
GERP RS		5.4
Varity_R		0.14
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: rs204900; hg19: chr6-32056580; COSMIC: COSV64478137; COSMIC: COSV64478137;