rs185819

Variant names:

• chr6-32082290-T-C
• rs185819
• NM_001365276.2:c.3482A>G

Your query was ambiguous. Multiple possible variants found:

• chr6-32082290-T-C
• chr6-32082290-T-A
• chr6-32082290-T-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.3482A>G​(p.His1161Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.515 in 1,600,200 control chromosomes in the GnomAD database, including 218,831 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H1161Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.52 (21130 hom., cov: 31)
  • Exomes 𝑓: 0.51 (197701 hom.)
• Consequence: TNXB NM_001365276.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.02
• Publications: 98 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)

ENSG00000294466 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.6441596E-6).
• BP6: Variant 6-32082290-T-C is Benign according to our data. Variant chr6-32082290-T-C is described in ClinVar as Benign. ClinVar VariationId is 261136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.694 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.3482A>G	p.His1161Arg	missense	Exon 9 of 44	NP_001352205.1	P22105-3
	TNXB	NM_001428335.1		c.4223A>G	p.His1408Arg	missense	Exon 10 of 45	NP_001415264.1	A0A3B3ISX9
	TNXB	NM_019105.8		c.3482A>G	p.His1161Arg	missense	Exon 9 of 44	NP_061978.6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNXB	ENST00000644971.2	MANE Select	c.3482A>G	p.His1161Arg	missense	Exon 9 of 44	ENSP00000496448.1	P22105-3
	TNXB	ENST00000647633.1		c.4223A>G	p.His1408Arg	missense	Exon 10 of 45	ENSP00000497649.1	A0A3B3ISX9
	TNXB	ENST00000375244.7	TSL:5	c.3482A>G	p.His1161Arg	missense	Exon 9 of 44	ENSP00000364393.3	P22105-3

Frequencies

GnomAD3 genomes AF: 0.521 AC: 79040 AN: 151592 Hom.: 21116 Cov.: 31

Gnomad AFR AF: 0.464

Gnomad AMI AF: 0.618

Gnomad AMR AF: 0.606

Gnomad ASJ AF: 0.669

Gnomad EAS AF: 0.616

Gnomad SAS AF: 0.715

Gnomad FIN AF: 0.537

Gnomad MID AF: 0.680

Gnomad NFE AF: 0.504

Gnomad OTH AF: 0.541

GnomAD2 exomes AF: 0.577 AC: 140385 AN: 243330 AF XY: 0.586

Gnomad AFR exome AF: 0.464

Gnomad AMR exome AF: 0.662

Gnomad ASJ exome AF: 0.670

Gnomad EAS exome AF: 0.601

Gnomad FIN exome AF: 0.532

Gnomad NFE exome AF: 0.515

Gnomad OTH exome AF: 0.556

GnomAD4 exome AF: 0.515 AC: 745395 AN: 1448488 Hom.: 197701 Cov.: 50 AF XY: 0.523 AC XY: 375931 AN XY: 718670

African (AFR) AF: 0.475 AC: 15825 AN: 33330

American (AMR) AF: 0.657 AC: 29297 AN: 44586

Ashkenazi Jewish (ASJ) AF: 0.663 AC: 17219 AN: 25980

East Asian (EAS) AF: 0.635 AC: 25088 AN: 39488

South Asian (SAS) AF: 0.742 AC: 63147 AN: 85096

European-Finnish (FIN) AF: 0.525 AC: 26357 AN: 50230

Middle Eastern (MID) AF: 0.674 AC: 3730 AN: 5534

European-Non Finnish (NFE) AF: 0.483 AC: 533316 AN: 1104406

Other (OTH) AF: 0.525 AC: 31416 AN: 59838

GnomAD4 genome AF: 0.521 AC: 79102 AN: 151712 Hom.: 21130 Cov.: 31 AF XY: 0.531 AC XY: 39340 AN XY: 74148

African (AFR) AF: 0.465 AC: 19186 AN: 41300

American (AMR) AF: 0.606 AC: 9258 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.669 AC: 2322 AN: 3472

East Asian (EAS) AF: 0.617 AC: 3169 AN: 5138

South Asian (SAS) AF: 0.714 AC: 3434 AN: 4812

European-Finnish (FIN) AF: 0.537 AC: 5663 AN: 10542

Middle Eastern (MID) AF: 0.656 AC: 193 AN: 294

European-Non Finnish (NFE) AF: 0.504 AC: 34179 AN: 67870

Other (OTH) AF: 0.539 AC: 1134 AN: 2104

Alfa AF: 0.524 Hom.: 90065

Bravo AF: 0.523

TwinsUK AF: 0.478 AC: 1773

ALSPAC AF: 0.478 AC: 1843

ESP6500AA AF: 0.458 AC: 1134

ESP6500EA AF: 0.486 AC: 2474

ExAC AF: 0.574 AC: 66938

Asia WGS AF: 0.651 AC: 2267 AN: 3478

EpiCase AF: 0.539

EpiControl AF: 0.543

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	Ehlers-Danlos syndrome due to tenascin-X deficiency (1)
-	-	1	Vesicoureteral reflux 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	11
DANN	Benign	0.69
DEOGEN2	Benign	0.012	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.023	T
MetaRNN	Benign	0.0000016	T
MetaSVM	Benign	-0.96	T
PhyloP100		2.0
PrimateAI	Benign	0.47	T
PROVEAN	Benign	1.5	N
REVEL	Benign	0.065
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.069
ClinPred		0.00083	T
GERP RS		4.0
Varity_R		0.048
Mutation Taster		=99/1	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: rs185819; hg19: chr6-32050067; COSMIC: COSV64481722; COSMIC: COSV64481722;