6-32084667-C-T

Variant names:

• chr6-32084667-C-T
• rs61995676
• NM_001365276.2:c.3191G>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.3191G>A​(p.Arg1064His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0148 in 1,591,792 control chromosomes in the GnomAD database, including 251 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. R1064C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.013 (27 hom., cov: 32)
  • Exomes 𝑓: 0.015 (224 hom.)
• Consequence: TNXB NM_001365276.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.00200
• Publications: 13 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=0.0064964592).
• BP6: Variant 6-32084667-C-T is Benign according to our data. Variant chr6-32084667-C-T is described in ClinVar as Benign. ClinVar VariationId is 261133.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 = 0.0126 (1926/152304) while in subpopulation NFE AF = 0.0198 (1345/68020). AF 95% confidence interval is 0.0189. There are 27 homozygotes in GnomAd4. There are 952 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 27 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.3191G>A	p.Arg1064His	missense	Exon 8 of 44	NP_001352205.1	P22105-3
	TNXB	NM_001428335.1		c.3932G>A	p.Arg1311His	missense	Exon 9 of 45	NP_001415264.1	A0A3B3ISX9
	TNXB	NM_019105.8		c.3191G>A	p.Arg1064His	missense	Exon 8 of 44	NP_061978.6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNXB	ENST00000644971.2	MANE Select	c.3191G>A	p.Arg1064His	missense	Exon 8 of 44	ENSP00000496448.1	P22105-3
	TNXB	ENST00000647633.1		c.3932G>A	p.Arg1311His	missense	Exon 9 of 45	ENSP00000497649.1	A0A3B3ISX9
	TNXB	ENST00000375244.7	TSL:5	c.3191G>A	p.Arg1064His	missense	Exon 8 of 44	ENSP00000364393.3	P22105-3

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1926 AN: 152186 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.00367

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0316

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0198

Gnomad OTH AF: 0.00764

GnomAD2 exomes AF: 0.0132 AC: 3126 AN: 236734 AF XY: 0.0131

Gnomad AFR exome AF: 0.00290

Gnomad AMR exome AF: 0.00184

Gnomad ASJ exome AF: 0.00114

Gnomad EAS exome AF: 0.000114

Gnomad FIN exome AF: 0.0298

Gnomad NFE exome AF: 0.0219

Gnomad OTH exome AF: 0.0105

GnomAD4 exome AF: 0.0150 AC: 21579 AN: 1439488 Hom.: 224 Cov.: 31 AF XY: 0.0143 AC XY: 10215 AN XY: 712628

African (AFR) AF: 0.00223 AC: 74 AN: 33222

American (AMR) AF: 0.00209 AC: 92 AN: 44026

Ashkenazi Jewish (ASJ) AF: 0.00124 AC: 32 AN: 25760

East Asian (EAS) AF: 0.000331 AC: 13 AN: 39258

South Asian (SAS) AF: 0.000357 AC: 30 AN: 83934

European-Finnish (FIN) AF: 0.0293 AC: 1440 AN: 49154

Middle Eastern (MID) AF: 0.00192 AC: 11 AN: 5722

European-Non Finnish (NFE) AF: 0.0175 AC: 19259 AN: 1098956

Other (OTH) AF: 0.0106 AC: 628 AN: 59456

GnomAD4 genome AF: 0.0126 AC: 1926 AN: 152304 Hom.: 27 Cov.: 32 AF XY: 0.0128 AC XY: 952 AN XY: 74478

African (AFR) AF: 0.00366 AC: 152 AN: 41562

American (AMR) AF: 0.00235 AC: 36 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.0316 AC: 336 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0198 AC: 1345 AN: 68020

Other (OTH) AF: 0.00756 AC: 16 AN: 2116

Alfa AF: 0.0169 Hom.: 109

Bravo AF: 0.0105

TwinsUK AF: 0.0165 AC: 61

ALSPAC AF: 0.0195 AC: 75

ESP6500AA AF: 0.00416 AC: 12

ESP6500EA AF: 0.0154 AC: 82

ExAC AF: 0.0147 AC: 1753

Asia WGS AF: 0.000577 AC: 2 AN: 3478

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	0.078
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	20
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.23	T
Eigen	Benign	0.12
Eigen_PC	Benign	-0.097
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0065	T
MetaSVM	Benign	-0.90	T
PhyloP100		0.0020
PrimateAI	Benign	0.23	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.17
Sift	Uncertain	0.026	D
Sift4G	Uncertain	0.0090	D
Vest4		0.062
ClinPred		0.032	T
GERP RS		1.2
Varity_R		0.089
Mutation Taster		=100/0	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: rs61995676; hg19: chr6-32052444;