6-32049366-C-T

Variant names:

• chr6-32049366-C-T
• rs367685759
• NM_001365276.2:c.9661G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001365276.2(TNXB):​c.9661G>A​(p.Val3221Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00262 in 1,612,516 control chromosomes in the GnomAD database, including 151 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V3221F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0028 (151 hom.)
• Consequence: TNXB NM_001365276.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: -0.0220
• Publications: 1 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027631521).
• BP6: Variant 6-32049366-C-T is Benign according to our data. Variant chr6-32049366-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 209196.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00129 (197/152312) while in subpopulation SAS AF = 0.0371 (179/4826). AF 95% confidence interval is 0.0327. There are 0 homozygotes in GnomAd4. There are 137 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 151 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.9661G>A	p.Val3221Met	missense	Exon 28 of 44	NP_001352205.1	P22105-3
	TNXB	NM_001428335.1		c.10402G>A	p.Val3468Met	missense	Exon 29 of 45	NP_001415264.1	A0A3B3ISX9
	TNXB	NM_019105.8		c.9655G>A	p.Val3219Met	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.9661G>A	p.Val3221Met	missense	Exon 28 of 44	ENSP00000496448.1	P22105-3
	TNXB	ENST00000647633.1		c.10402G>A	p.Val3468Met	missense	Exon 29 of 45	ENSP00000497649.1	A0A3B3ISX9
	TNXB	ENST00000375244.7	TSL:5	c.9661G>A	p.Val3221Met	missense	Exon 28 of 44	ENSP00000364393.3	P22105-3

Frequencies

GnomAD3 genomes AF: 0.00131 AC: 199 AN: 152194 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0375

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00590 AC: 1458 AN: 247064 AF XY: 0.00790

Gnomad AFR exome AF: 0.000269

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000430

Gnomad OTH exome AF: 0.00465

GnomAD4 exome AF: 0.00276 AC: 4035 AN: 1460204 Hom.: 151 Cov.: 32 AF XY: 0.00399 AC XY: 2895 AN XY: 726440

African (AFR) AF: 0.000329 AC: 11 AN: 33442

American (AMR) AF: 0.000112 AC: 5 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0409 AC: 3521 AN: 86186

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53312

Middle Eastern (MID) AF: 0.000647 AC: 3 AN: 4636

European-Non Finnish (NFE) AF: 0.000246 AC: 273 AN: 1111850

Other (OTH) AF: 0.00365 AC: 220 AN: 60250

GnomAD4 genome AF: 0.00129 AC: 197 AN: 152312 Hom.: 0 Cov.: 33 AF XY: 0.00184 AC XY: 137 AN XY: 74478

African (AFR) AF: 0.000120 AC: 5 AN: 41562

American (AMR) AF: 0.0000653 AC: 1 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.0371 AC: 179 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68014

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.000244 Hom.: 1

Bravo AF: 0.000317

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000393 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00643 AC: 776

Asia WGS AF: 0.0270 AC: 92 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Ehlers-Danlos syndrome (1)
-	1	-	Ehlers-Danlos syndrome due to tenascin-X deficiency (1)
-	-	1	not specified (1)
-	1	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.044	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-0.81	T
PhyloP100		-0.022
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.12
Sift	Benign	0.033	D
Sift4G	Uncertain	0.0020	D
Vest4		0.35
MVP		0.15
ClinPred		0.022	T
GERP RS		0.37
Varity_R		0.048
Mutation Taster		=98/2	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: rs367685759; hg19: chr6-32017143; COSMIC: COSV64492935; COSMIC: COSV64492935;