6-32079167-C-T

Variant names:

• chr6-32079167-C-T
• rs9267799
• NM_001365276.2:c.4241G>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.4241G>A​(p.Arg1414Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.021 in 1,613,816 control chromosomes in the GnomAD database, including 660 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. R1414W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.033 (157 hom., cov: 32)
  • Exomes 𝑓: 0.020 (503 hom.)
• Consequence: TNXB NM_001365276.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.27
• Publications: 14 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=0.0019538403).
• BP6: Variant 6-32079167-C-T is Benign according to our data. Variant chr6-32079167-C-T is described in ClinVar as Benign. ClinVar VariationId is 261138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0645 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.4241G>A	p.Arg1414Gln	missense	Exon 11 of 44	NP_001352205.1	P22105-3
	TNXB	NM_001428335.1		c.4982G>A	p.Arg1661Gln	missense	Exon 12 of 45	NP_001415264.1	A0A3B3ISX9
	TNXB	NM_019105.8		c.4241G>A	p.Arg1414Gln	missense	Exon 11 of 44	NP_061978.6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNXB	ENST00000644971.2	MANE Select	c.4241G>A	p.Arg1414Gln	missense	Exon 11 of 44	ENSP00000496448.1	P22105-3
	TNXB	ENST00000647633.1		c.4982G>A	p.Arg1661Gln	missense	Exon 12 of 45	ENSP00000497649.1	A0A3B3ISX9
	TNXB	ENST00000375244.7	TSL:5	c.4241G>A	p.Arg1414Gln	missense	Exon 11 of 44	ENSP00000364393.3	P22105-3

Frequencies

GnomAD3 genomes AF: 0.0335 AC: 5092 AN: 152196 Hom.: 158 Cov.: 32

Gnomad AFR AF: 0.0667

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0351

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.0614

Gnomad SAS AF: 0.0408

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0163

Gnomad OTH AF: 0.0431

GnomAD2 exomes AF: 0.0272 AC: 6735 AN: 247422 AF XY: 0.0276

Gnomad AFR exome AF: 0.0673

Gnomad AMR exome AF: 0.0260

Gnomad ASJ exome AF: 0.0133

Gnomad EAS exome AF: 0.0777

Gnomad FIN exome AF: 0.00311

Gnomad NFE exome AF: 0.0158

Gnomad OTH exome AF: 0.0251

GnomAD4 exome AF: 0.0197 AC: 28781 AN: 1461502 Hom.: 503 Cov.: 32 AF XY: 0.0202 AC XY: 14722 AN XY: 727036

African (AFR) AF: 0.0664 AC: 2223 AN: 33476

American (AMR) AF: 0.0270 AC: 1208 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0122 AC: 318 AN: 26134

East Asian (EAS) AF: 0.0332 AC: 1317 AN: 39700

South Asian (SAS) AF: 0.0436 AC: 3763 AN: 86254

European-Finnish (FIN) AF: 0.00379 AC: 202 AN: 53360

Middle Eastern (MID) AF: 0.0284 AC: 160 AN: 5632

European-Non Finnish (NFE) AF: 0.0164 AC: 18283 AN: 1111866

Other (OTH) AF: 0.0217 AC: 1307 AN: 60356

GnomAD4 genome AF: 0.0335 AC: 5099 AN: 152314 Hom.: 157 Cov.: 32 AF XY: 0.0328 AC XY: 2444 AN XY: 74492

African (AFR) AF: 0.0666 AC: 2766 AN: 41558

American (AMR) AF: 0.0350 AC: 536 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 39 AN: 3470

East Asian (EAS) AF: 0.0617 AC: 320 AN: 5184

South Asian (SAS) AF: 0.0412 AC: 199 AN: 4830

European-Finnish (FIN) AF: 0.00235 AC: 25 AN: 10628

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0163 AC: 1108 AN: 68020

Other (OTH) AF: 0.0426 AC: 90 AN: 2112

Alfa AF: 0.0203 Hom.: 27

Bravo AF: 0.0369

TwinsUK AF: 0.0129 AC: 48

ALSPAC AF: 0.0163 AC: 63

ESP6500AA AF: 0.0626 AC: 161

ESP6500EA AF: 0.0186 AC: 95

ExAC AF: 0.0278 AC: 3356

Asia WGS AF: 0.0390 AC: 134 AN: 3478

EpiCase AF: 0.0188

EpiControl AF: 0.0214

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	0.056
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	9.9
DANN	Benign	0.77
DEOGEN2	Benign	0.022	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.37	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-0.97	T
PhyloP100		1.3
PrimateAI	Benign	0.32	T
PROVEAN	Benign	1.7	N
REVEL	Benign	0.15
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.021
ClinPred		0.0013	T
GERP RS		4.3
Varity_R		0.030
Mutation Taster		=96/4	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: rs9267799; hg19: chr6-32046944;