rs204896

Variant names:

• chr6-32096321-C-T
• rs204896
• NM_001365276.2:c.1532G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-32096321-C-T
• chr6-32096321-C-A

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.1532G>A​(p.Arg511His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 1,548,246 control chromosomes in the GnomAD database, including 13,959 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R511R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.15 (2281 hom., cov: 34)
  • Exomes 𝑓: 0.11 (11678 hom.)
• Consequence: TNXB NM_001365276.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.146
• Publications: 18 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=0.0062685013).
• BP6: Variant 6-32096321-C-T is Benign according to our data. Variant chr6-32096321-C-T is described in ClinVar as Benign. ClinVar VariationId is 261125.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.276 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.1532G>A	p.Arg511His	missense	Exon 3 of 44	NP_001352205.1	P22105-3
	TNXB	NM_001428335.1		c.1532G>A	p.Arg511His	missense	Exon 3 of 45	NP_001415264.1	A0A3B3ISX9
	TNXB	NM_019105.8		c.1532G>A	p.Arg511His	missense	Exon 3 of 44	NP_061978.6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNXB	ENST00000644971.2	MANE Select	c.1532G>A	p.Arg511His	missense	Exon 3 of 44	ENSP00000496448.1	P22105-3
	TNXB	ENST00000479795.1	TSL:1	c.1532G>A	p.Arg511His	missense	Exon 3 of 5	ENSP00000418248.1	C9J7W4
	TNXB	ENST00000486148.1	TSL:1	n.1927G>A		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.150 AC: 22858 AN: 152132 Hom.: 2268 Cov.: 34

Gnomad AFR AF: 0.258

Gnomad AMI AF: 0.0165

Gnomad AMR AF: 0.148

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.106

Gnomad SAS AF: 0.289

Gnomad FIN AF: 0.0623

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.0945

Gnomad OTH AF: 0.187

GnomAD2 exomes AF: 0.147 AC: 21664 AN: 146980 AF XY: 0.161

Gnomad AFR exome AF: 0.266

Gnomad AMR exome AF: 0.101

Gnomad ASJ exome AF: 0.104

Gnomad EAS exome AF: 0.105

Gnomad FIN exome AF: 0.0701

Gnomad NFE exome AF: 0.100

Gnomad OTH exome AF: 0.140

GnomAD4 exome AF: 0.109 AC: 152312 AN: 1395996 Hom.: 11678 Cov.: 33 AF XY: 0.116 AC XY: 80076 AN XY: 689910

African (AFR) AF: 0.266 AC: 8477 AN: 31866

American (AMR) AF: 0.106 AC: 3894 AN: 36610

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 2701 AN: 25288

East Asian (EAS) AF: 0.108 AC: 3888 AN: 36166

South Asian (SAS) AF: 0.330 AC: 26379 AN: 79956

European-Finnish (FIN) AF: 0.0697 AC: 2641 AN: 37912

Middle Eastern (MID) AF: 0.256 AC: 1459 AN: 5696

European-Non Finnish (NFE) AF: 0.0883 AC: 95708 AN: 1084208

Other (OTH) AF: 0.123 AC: 7165 AN: 58294

GnomAD4 genome AF: 0.150 AC: 22895 AN: 152250 Hom.: 2281 Cov.: 34 AF XY: 0.153 AC XY: 11409 AN XY: 74446

African (AFR) AF: 0.259 AC: 10763 AN: 41538

American (AMR) AF: 0.148 AC: 2265 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 371 AN: 3472

East Asian (EAS) AF: 0.105 AC: 546 AN: 5180

South Asian (SAS) AF: 0.289 AC: 1395 AN: 4826

European-Finnish (FIN) AF: 0.0623 AC: 662 AN: 10618

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.0945 AC: 6424 AN: 68004

Other (OTH) AF: 0.184 AC: 388 AN: 2112

Alfa AF: 0.109 Hom.: 2539

Bravo AF: 0.157

TwinsUK AF: 0.0852 AC: 316

ALSPAC AF: 0.0947 AC: 365

ESP6500AA AF: 0.229 AC: 940

ESP6500EA AF: 0.0855 AC: 694

ExAC AF: 0.107 AC: 11845

Asia WGS AF: 0.244 AC: 851 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.032	N
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0063	T
MetaSVM	Benign	-0.98	T
PhyloP100		0.15
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.054
Sift	Benign	0.032	D
Sift4G	Uncertain	0.0030	D
Vest4		0.099
ClinPred		0.027	T
GERP RS		2.3
Varity_R		0.17
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: rs204896; hg19: chr6-32064098; COSMIC: COSV64472710; COSMIC: COSV64472710;