rs41258944

Variant names:

• chr6-32049465-C-T
• rs41258944
• NM_001365276.2:c.9562G>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.9562G>A​(p.Val3188Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0594 in 1,612,640 control chromosomes in the GnomAD database, including 3,258 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.068 (416 hom., cov: 32)
  • Exomes 𝑓: 0.059 (2842 hom.)
• Consequence: TNXB NM_001365276.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0390
• Publications: 10 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=0.0017081797).
• BP6: Variant 6-32049465-C-T is Benign according to our data. Variant chr6-32049465-C-T is described in ClinVar as Benign. ClinVar VariationId is 261178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.108 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.9562G>A	p.Val3188Ile	missense	Exon 28 of 44	NP_001352205.1	P22105-3
	TNXB	NM_001428335.1		c.10303G>A	p.Val3435Ile	missense	Exon 29 of 45	NP_001415264.1	A0A3B3ISX9
	TNXB	NM_019105.8		c.9556G>A	p.Val3186Ile	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.9562G>A	p.Val3188Ile	missense	Exon 28 of 44	ENSP00000496448.1	P22105-3
	TNXB	ENST00000647633.1		c.10303G>A	p.Val3435Ile	missense	Exon 29 of 45	ENSP00000497649.1	A0A3B3ISX9
	TNXB	ENST00000375244.7	TSL:5	c.9562G>A	p.Val3188Ile	missense	Exon 28 of 44	ENSP00000364393.3	P22105-3

Frequencies

GnomAD3 genomes AF: 0.0676 AC: 10283 AN: 152098 Hom.: 418 Cov.: 32

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.157

Gnomad AMR AF: 0.0362

Gnomad ASJ AF: 0.0692

Gnomad EAS AF: 0.00886

Gnomad SAS AF: 0.0605

Gnomad FIN AF: 0.0188

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0598

Gnomad OTH AF: 0.0636

GnomAD2 exomes AF: 0.0484 AC: 11881 AN: 245582 AF XY: 0.0496

Gnomad AFR exome AF: 0.118

Gnomad AMR exome AF: 0.0290

Gnomad ASJ exome AF: 0.0720

Gnomad EAS exome AF: 0.00290

Gnomad FIN exome AF: 0.0192

Gnomad NFE exome AF: 0.0539

Gnomad OTH exome AF: 0.0479

GnomAD4 exome AF: 0.0585 AC: 85459 AN: 1460424 Hom.: 2842 Cov.: 34 AF XY: 0.0578 AC XY: 42006 AN XY: 726510

African (AFR) AF: 0.117 AC: 3925 AN: 33446

American (AMR) AF: 0.0317 AC: 1416 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0739 AC: 1931 AN: 26136

East Asian (EAS) AF: 0.00224 AC: 89 AN: 39700

South Asian (SAS) AF: 0.0548 AC: 4722 AN: 86222

European-Finnish (FIN) AF: 0.0211 AC: 1117 AN: 52958

Middle Eastern (MID) AF: 0.0499 AC: 255 AN: 5110

European-Non Finnish (NFE) AF: 0.0613 AC: 68181 AN: 1111846

Other (OTH) AF: 0.0634 AC: 3823 AN: 60282

GnomAD4 genome AF: 0.0676 AC: 10291 AN: 152216 Hom.: 416 Cov.: 32 AF XY: 0.0644 AC XY: 4790 AN XY: 74414

African (AFR) AF: 0.111 AC: 4610 AN: 41516

American (AMR) AF: 0.0362 AC: 553 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0692 AC: 240 AN: 3470

East Asian (EAS) AF: 0.00888 AC: 46 AN: 5180

South Asian (SAS) AF: 0.0599 AC: 289 AN: 4826

European-Finnish (FIN) AF: 0.0188 AC: 199 AN: 10610

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0598 AC: 4064 AN: 68002

Other (OTH) AF: 0.0630 AC: 133 AN: 2112

Alfa AF: 0.0652 Hom.: 151

Bravo AF: 0.0714

TwinsUK AF: 0.0601 AC: 223

ALSPAC AF: 0.0586 AC: 226

ESP6500AA AF: 0.113 AC: 283

ESP6500EA AF: 0.0622 AC: 313

ExAC AF: 0.0494 AC: 5915

EpiCase AF: 0.0623

EpiControl AF: 0.0580

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Cardiovascular phenotype (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.015	T
Eigen	Benign	0.14
Eigen_PC	Benign	0.032
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.35	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.84	T
PhyloP100		0.039
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.14
Sift	Benign	0.22	T
Sift4G	Benign	0.21	T
Vest4		0.076
ClinPred		0.0063	T
GERP RS		3.5
Varity_R		0.028
Mutation Taster		=98/2	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: rs41258944; hg19: chr6-32017242; COSMIC: COSV100926265; COSMIC: COSV100926265;