NM_001365276.2:c.6811G>C

Variant names:

• chr6-32064851-C-G
• rs140770834
• NM_001365276.2:c.6811G>C

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.6811G>C​(p.Val2271Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00523 in 1,611,140 control chromosomes in the GnomAD database, including 106 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0049 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0053 (102 hom.)
• Consequence: TNXB NM_001365276.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.25
• Publications: 11 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=0.004063517).
• BP6: Variant 6-32064851-C-G is Benign according to our data. Variant chr6-32064851-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00486 (740/152332) while in subpopulation EAS AF = 0.0135 (70/5180). AF 95% confidence interval is 0.011. There are 4 homozygotes in GnomAd4. There are 399 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.6811G>C	p.Val2271Leu	missense	Exon 19 of 44	NP_001352205.1	P22105-3
	TNXB	NM_001428335.1		c.7552G>C	p.Val2518Leu	missense	Exon 20 of 45	NP_001415264.1	A0A3B3ISX9
	TNXB	NM_019105.8		c.6811G>C	p.Val2271Leu	missense	Exon 19 of 44	NP_061978.6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNXB	ENST00000644971.2	MANE Select	c.6811G>C	p.Val2271Leu	missense	Exon 19 of 44	ENSP00000496448.1	P22105-3
	TNXB	ENST00000647633.1		c.7552G>C	p.Val2518Leu	missense	Exon 20 of 45	ENSP00000497649.1	A0A3B3ISX9
	TNXB	ENST00000375244.7	TSL:5	c.6811G>C	p.Val2271Leu	missense	Exon 19 of 44	ENSP00000364393.3	P22105-3

Frequencies

GnomAD3 genomes AF: 0.00487 AC: 741 AN: 152214 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00661

Gnomad ASJ AF: 0.0251

Gnomad EAS AF: 0.0135

Gnomad SAS AF: 0.0135

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00485

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00653 AC: 1591 AN: 243792 AF XY: 0.00731

Gnomad AFR exome AF: 0.000628

Gnomad AMR exome AF: 0.00448

Gnomad ASJ exome AF: 0.0283

Gnomad EAS exome AF: 0.0115

Gnomad FIN exome AF: 0.000511

Gnomad NFE exome AF: 0.00453

Gnomad OTH exome AF: 0.0110

GnomAD4 exome AF: 0.00526 AC: 7680 AN: 1458808 Hom.: 102 Cov.: 30 AF XY: 0.00568 AC XY: 4119 AN XY: 725718

African (AFR) AF: 0.00206 AC: 69 AN: 33448

American (AMR) AF: 0.00481 AC: 215 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0296 AC: 772 AN: 26104

East Asian (EAS) AF: 0.0400 AC: 1588 AN: 39696

South Asian (SAS) AF: 0.0119 AC: 1027 AN: 86050

European-Finnish (FIN) AF: 0.000710 AC: 37 AN: 52084

Middle Eastern (MID) AF: 0.0235 AC: 120 AN: 5104

European-Non Finnish (NFE) AF: 0.00311 AC: 3459 AN: 1111344

Other (OTH) AF: 0.00652 AC: 393 AN: 60264

GnomAD4 genome AF: 0.00486 AC: 740 AN: 152332 Hom.: 4 Cov.: 32 AF XY: 0.00536 AC XY: 399 AN XY: 74492

African (AFR) AF: 0.00149 AC: 62 AN: 41566

American (AMR) AF: 0.00660 AC: 101 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0251 AC: 87 AN: 3472

East Asian (EAS) AF: 0.0135 AC: 70 AN: 5180

South Asian (SAS) AF: 0.0135 AC: 65 AN: 4828

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10618

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00485 AC: 330 AN: 68042

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

Alfa AF: 0.00708 Hom.: 11

Bravo AF: 0.00521

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000797 AC: 2

ESP6500EA AF: 0.00588 AC: 30

ExAC AF: 0.00622 AC: 736

Asia WGS AF: 0.0110 AC: 39 AN: 3478

EpiCase AF: 0.00649

EpiControl AF: 0.00747

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.0040
DANN	Benign	0.81
DEOGEN2	Benign	0.034	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0035	N
LIST_S2	Benign	0.077	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-0.91	T
PhyloP100		-2.2
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.89	N
REVEL	Benign	0.025
Sift	Benign	0.30	T
Sift4G	Benign	0.28	T
Vest4		0.057
MVP		0.12
ClinPred		0.0038	T
GERP RS		-8.3
Varity_R		0.070
Mutation Taster		=100/0	polymorphism

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: rs140770834; hg19: chr6-32032628; COSMIC: COSV108903350; COSMIC: COSV108903350;