6-32058330-C-T

Variant names:

• chr6-32058330-C-T
• rs1009382
• NM_001365276.2:c.7553G>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.7553G>A​(p.Gly2518Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.711 in 1,611,184 control chromosomes in the GnomAD database, including 409,280 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 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. G2518G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.69 (36743 hom., cov: 31)
  • Exomes 𝑓: 0.71 (372537 hom.)
• Consequence: TNXB NM_001365276.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.350
• Publications: 45 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=9.462437E-7).
• BP6: Variant 6-32058330-C-T is Benign according to our data. Variant chr6-32058330-C-T is described in ClinVar as Benign. ClinVar VariationId is 261162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.75 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.7553G>A	p.Gly2518Glu	missense	Exon 22 of 44	NP_001352205.1	P22105-3
	TNXB	NM_001428335.1		c.8294G>A	p.Gly2765Glu	missense	Exon 23 of 45	NP_001415264.1	A0A3B3ISX9
	TNXB	NM_019105.8		c.7553G>A	p.Gly2518Glu	missense	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.7553G>A	p.Gly2518Glu	missense	Exon 22 of 44	ENSP00000496448.1	P22105-3
	TNXB	ENST00000647633.1		c.8294G>A	p.Gly2765Glu	missense	Exon 23 of 45	ENSP00000497649.1	A0A3B3ISX9
	TNXB	ENST00000375244.7	TSL:5	c.7553G>A	p.Gly2518Glu	missense	Exon 22 of 44	ENSP00000364393.3	P22105-3

Frequencies

GnomAD3 genomes AF: 0.692 AC: 104635 AN: 151308 Hom.: 36712 Cov.: 31

Gnomad AFR AF: 0.635

Gnomad AMI AF: 0.737

Gnomad AMR AF: 0.761

Gnomad ASJ AF: 0.852

Gnomad EAS AF: 0.634

Gnomad SAS AF: 0.748

Gnomad FIN AF: 0.651

Gnomad MID AF: 0.788

Gnomad NFE AF: 0.707

Gnomad OTH AF: 0.722

GnomAD2 exomes AF: 0.720 AC: 173470 AN: 240990 AF XY: 0.724

Gnomad AFR exome AF: 0.639

Gnomad AMR exome AF: 0.783

Gnomad ASJ exome AF: 0.848

Gnomad EAS exome AF: 0.617

Gnomad FIN exome AF: 0.651

Gnomad NFE exome AF: 0.711

Gnomad OTH exome AF: 0.724

GnomAD4 exome AF: 0.713 AC: 1040295 AN: 1459760 Hom.: 372537 Cov.: 65 AF XY: 0.716 AC XY: 519633 AN XY: 726150

African (AFR) AF: 0.647 AC: 21615 AN: 33410

American (AMR) AF: 0.783 AC: 34953 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.845 AC: 22063 AN: 26124

East Asian (EAS) AF: 0.655 AC: 25994 AN: 39690

South Asian (SAS) AF: 0.775 AC: 66874 AN: 86244

European-Finnish (FIN) AF: 0.648 AC: 33653 AN: 51958

Middle Eastern (MID) AF: 0.772 AC: 4447 AN: 5764

European-Non Finnish (NFE) AF: 0.709 AC: 787688 AN: 1111586

Other (OTH) AF: 0.713 AC: 43008 AN: 60322

GnomAD4 genome AF: 0.692 AC: 104717 AN: 151424 Hom.: 36743 Cov.: 31 AF XY: 0.691 AC XY: 51152 AN XY: 74010

African (AFR) AF: 0.635 AC: 25977 AN: 40892

American (AMR) AF: 0.761 AC: 11627 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.852 AC: 2958 AN: 3470

East Asian (EAS) AF: 0.635 AC: 3275 AN: 5156

South Asian (SAS) AF: 0.746 AC: 3589 AN: 4812

European-Finnish (FIN) AF: 0.651 AC: 6871 AN: 10562

Middle Eastern (MID) AF: 0.776 AC: 228 AN: 294

European-Non Finnish (NFE) AF: 0.707 AC: 48012 AN: 67952

Other (OTH) AF: 0.719 AC: 1509 AN: 2100

Alfa AF: 0.708 Hom.: 19963

Bravo AF: 0.699

TwinsUK AF: 0.714 AC: 2647

ALSPAC AF: 0.710 AC: 2736

ESP6500AA AF: 0.652 AC: 1507

ESP6500EA AF: 0.701 AC: 3513

ExAC AF: 0.714 AC: 83884

Asia WGS AF: 0.693 AC: 2414 AN: 3478

EpiCase AF: 0.730

EpiControl AF: 0.732

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Ehlers-Danlos syndrome due to tenascin-X deficiency (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	not provided (1)
-	-	1	Vesicoureteral reflux 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.85	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.077
DANN	Benign	0.16
DEOGEN2	Benign	0.022	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.00094	N
LIST_S2	Benign	0.034	T
MetaRNN	Benign	9.5e-7	T
MetaSVM	Benign	-0.95	T
PhyloP100		-0.35
PrimateAI	Benign	0.33	T
PROVEAN	Benign	2.3	N
REVEL	Benign	0.024
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.025
ClinPred		0.0011	T
GERP RS		3.3
Varity_R		0.025
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: rs1009382; hg19: chr6-32026107; COSMIC: COSV64485077;