6-32049396-G-C

Variant names:

• chr6-32049396-G-C
• rs41270450
• NM_001365276.2:c.9631C>G

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.9631C>G​(p.Arg3211Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0409 in 1,612,554 control chromosomes in the GnomAD database, including 1,923 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 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. R3211S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.038 (221 hom., cov: 32)
  • Exomes 𝑓: 0.041 (1702 hom.)
• Consequence: TNXB NM_001365276.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.41
• Publications: 7 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=0.0019940138).
• BP6: Variant 6-32049396-G-C is Benign according to our data. Variant chr6-32049396-G-C is described in ClinVar as Benign. ClinVar VariationId is 261179.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 = 0.0376 (5725/152236) while in subpopulation NFE AF = 0.0463 (3150/68008). AF 95% confidence interval is 0.045. There are 221 homozygotes in GnomAd4. There are 3072 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 221 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.9631C>G	p.Arg3211Gly	missense	Exon 28 of 44	NP_001352205.1	P22105-3
	TNXB	NM_001428335.1		c.10372C>G	p.Arg3458Gly	missense	Exon 29 of 45	NP_001415264.1	A0A3B3ISX9
	TNXB	NM_019105.8		c.9625C>G	p.Arg3209Gly	missense	Exon 28 of 44	NP_061978.6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNXB	ENST00000644971.2	MANE Select	c.9631C>G	p.Arg3211Gly	missense	Exon 28 of 44	ENSP00000496448.1	P22105-3
	TNXB	ENST00000647633.1		c.10372C>G	p.Arg3458Gly	missense	Exon 29 of 45	ENSP00000497649.1	A0A3B3ISX9
	TNXB	ENST00000375244.7	TSL:5	c.9631C>G	p.Arg3211Gly	missense	Exon 28 of 44	ENSP00000364393.3	P22105-3

Frequencies

GnomAD3 genomes AF: 0.0376 AC: 5724 AN: 152118 Hom.: 221 Cov.: 32

Gnomad AFR AF: 0.00729

Gnomad AMI AF: 0.0857

Gnomad AMR AF: 0.0229

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00405

Gnomad SAS AF: 0.0189

Gnomad FIN AF: 0.156

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0463

Gnomad OTH AF: 0.0263

GnomAD2 exomes AF: 0.0390 AC: 9626 AN: 246914 AF XY: 0.0392

Gnomad AFR exome AF: 0.00790

Gnomad AMR exome AF: 0.0152

Gnomad ASJ exome AF: 0.00530

Gnomad EAS exome AF: 0.00178

Gnomad FIN exome AF: 0.145

Gnomad NFE exome AF: 0.0458

Gnomad OTH exome AF: 0.0390

GnomAD4 exome AF: 0.0413 AC: 60306 AN: 1460318 Hom.: 1702 Cov.: 33 AF XY: 0.0406 AC XY: 29515 AN XY: 726464

African (AFR) AF: 0.00586 AC: 196 AN: 33444

American (AMR) AF: 0.0162 AC: 726 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00520 AC: 136 AN: 26130

East Asian (EAS) AF: 0.00136 AC: 54 AN: 39700

South Asian (SAS) AF: 0.0154 AC: 1328 AN: 86204

European-Finnish (FIN) AF: 0.140 AC: 7443 AN: 53284

Middle Eastern (MID) AF: 0.0286 AC: 135 AN: 4718

European-Non Finnish (NFE) AF: 0.0435 AC: 48354 AN: 1111856

Other (OTH) AF: 0.0321 AC: 1934 AN: 60258

GnomAD4 genome AF: 0.0376 AC: 5725 AN: 152236 Hom.: 221 Cov.: 32 AF XY: 0.0413 AC XY: 3072 AN XY: 74420

African (AFR) AF: 0.00727 AC: 302 AN: 41542

American (AMR) AF: 0.0229 AC: 350 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3470

East Asian (EAS) AF: 0.00406 AC: 21 AN: 5178

South Asian (SAS) AF: 0.0195 AC: 94 AN: 4820

European-Finnish (FIN) AF: 0.156 AC: 1649 AN: 10586

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0463 AC: 3150 AN: 68008

Other (OTH) AF: 0.0260 AC: 55 AN: 2116

Alfa AF: 0.0310 Hom.: 28

Bravo AF: 0.0263

TwinsUK AF: 0.0426 AC: 158

ALSPAC AF: 0.0464 AC: 179

ESP6500AA AF: 0.0116 AC: 30

ESP6500EA AF: 0.0467 AC: 238

ExAC AF: 0.0389 AC: 4697

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.0440

EpiControl AF: 0.0415

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	0.13
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-0.94	T
PhyloP100		1.4
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-3.9	D
REVEL	Benign	0.23
Sift	Benign	0.39	T
Sift4G	Uncertain	0.015	D
Vest4		0.21
ClinPred		0.041	T
GERP RS		4.4
Varity_R		0.29
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs41270450; hg19: chr6-32017173;