6-32053637-C-T

Variant names:

• chr6-32053637-C-T
• rs61745355
• NM_001365276.2:c.8542G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001365276.2(TNXB):​c.8542G>A​(p.Gly2848Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.023 in 1,613,382 control chromosomes in the GnomAD database, including 962 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. G2848G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.024 (142 hom., cov: 31)
  • Exomes 𝑓: 0.023 (820 hom.)
• Consequence: TNXB NM_001365276.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.52
• Publications: 16 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=0.0023582876).
• BP6: Variant 6-32053637-C-T is Benign according to our data. Variant chr6-32053637-C-T is described in ClinVar as Benign. ClinVar VariationId is 261169.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0243 (3699/152204) while in subpopulation NFE AF = 0.0246 (1675/67996). AF 95% confidence interval is 0.0237. There are 142 homozygotes in GnomAd4. There are 2145 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 142 AR,AD gene

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.8542G>A	p.Gly2848Arg	missense	Exon 25 of 44	NP_001352205.1	P22105-3
	TNXB	NM_001428335.1		c.9283G>A	p.Gly3095Arg	missense	Exon 26 of 45	NP_001415264.1	A0A3B3ISX9
	TNXB	NM_019105.8		c.8536G>A	p.Gly2846Arg	missense	Exon 25 of 44	NP_061978.6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNXB	ENST00000644971.2	MANE Select	c.8542G>A	p.Gly2848Arg	missense	Exon 25 of 44	ENSP00000496448.1	P22105-3
	TNXB	ENST00000647633.1		c.9283G>A	p.Gly3095Arg	missense	Exon 26 of 45	ENSP00000497649.1	A0A3B3ISX9
	TNXB	ENST00000375244.7	TSL:5	c.8542G>A	p.Gly2848Arg	missense	Exon 25 of 44	ENSP00000364393.3	P22105-3

Frequencies

GnomAD3 genomes AF: 0.0243 AC: 3698 AN: 152086 Hom.: 142 Cov.: 31

Gnomad AFR AF: 0.00415

Gnomad AMI AF: 0.0855

Gnomad AMR AF: 0.0100

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00871

Gnomad FIN AF: 0.147

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0246

Gnomad OTH AF: 0.00863

GnomAD2 exomes AF: 0.0246 AC: 6047 AN: 245848 AF XY: 0.0240

Gnomad AFR exome AF: 0.00403

Gnomad AMR exome AF: 0.00519

Gnomad ASJ exome AF: 0.000200

Gnomad EAS exome AF: 0.000223

Gnomad FIN exome AF: 0.135

Gnomad NFE exome AF: 0.0237

Gnomad OTH exome AF: 0.0203

GnomAD4 exome AF: 0.0229 AC: 33428 AN: 1461178 Hom.: 820 Cov.: 33 AF XY: 0.0223 AC XY: 16194 AN XY: 726872

African (AFR) AF: 0.00293 AC: 98 AN: 33470

American (AMR) AF: 0.00546 AC: 244 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.000306 AC: 8 AN: 26134

East Asian (EAS) AF: 0.000378 AC: 15 AN: 39700

South Asian (SAS) AF: 0.00632 AC: 545 AN: 86256

European-Finnish (FIN) AF: 0.129 AC: 6862 AN: 53000

Middle Eastern (MID) AF: 0.00454 AC: 26 AN: 5726

European-Non Finnish (NFE) AF: 0.0222 AC: 24665 AN: 1111822

Other (OTH) AF: 0.0160 AC: 965 AN: 60352

GnomAD4 genome AF: 0.0243 AC: 3699 AN: 152204 Hom.: 142 Cov.: 31 AF XY: 0.0288 AC XY: 2145 AN XY: 74392

African (AFR) AF: 0.00414 AC: 172 AN: 41542

American (AMR) AF: 0.0100 AC: 153 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5182

South Asian (SAS) AF: 0.00892 AC: 43 AN: 4820

European-Finnish (FIN) AF: 0.147 AC: 1556 AN: 10586

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0246 AC: 1675 AN: 67996

Other (OTH) AF: 0.00854 AC: 18 AN: 2108

Alfa AF: 0.0126 Hom.: 9

Bravo AF: 0.0127

TwinsUK AF: 0.0189 AC: 70

ALSPAC AF: 0.0239 AC: 92

ESP6500AA AF: 0.00762 AC: 20

ESP6500EA AF: 0.0242 AC: 125

ExAC AF: 0.0233 AC: 2808

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0189

EpiControl AF: 0.0181

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.084	T
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-0.82	T
PhyloP100		3.5
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0060	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.19
ClinPred		0.033	T
GERP RS		4.4
Varity_R		0.34
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs61745355; hg19: chr6-32021414; COSMIC: COSV64480230;