chr6-32056873-G-A

Variant names:

• chr6-32056873-G-A
• rs183760368
• NM_001365276.2:c.7856C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001365276.2(TNXB):​c.7856C>T​(p.Pro2619Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000873 in 1,612,584 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P2619P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00079 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00088 (0 hom.)
• Consequence: TNXB NM_001365276.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:4
• Conservation: PhyloP100: 2.67
• 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.021029472).
• BP6: Variant 6-32056873-G-A is Benign according to our data. Variant chr6-32056873-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 521772.
• BS2: High Homozygotes in GnomAd4 at 2 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.7856C>T	p.Pro2619Leu	missense	Exon 23 of 44	NP_001352205.1	P22105-3
	TNXB	NM_001428335.1		c.8597C>T	p.Pro2866Leu	missense	Exon 24 of 45	NP_001415264.1	A0A3B3ISX9
	TNXB	NM_019105.8		c.7856C>T	p.Pro2619Leu	missense	Exon 23 of 44	NP_061978.6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNXB	ENST00000644971.2	MANE Select	c.7856C>T	p.Pro2619Leu	missense	Exon 23 of 44	ENSP00000496448.1	P22105-3
	TNXB	ENST00000647633.1		c.8597C>T	p.Pro2866Leu	missense	Exon 24 of 45	ENSP00000497649.1	A0A3B3ISX9
	TNXB	ENST00000375244.7	TSL:5	c.7856C>T	p.Pro2619Leu	missense	Exon 23 of 44	ENSP00000364393.3	P22105-3

Frequencies

GnomAD3 genomes AF: 0.000749 AC: 114 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00129

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000888 AC: 218 AN: 245398 AF XY: 0.000918

Gnomad AFR exome AF: 0.000274

Gnomad AMR exome AF: 0.00102

Gnomad ASJ exome AF: 0.00171

Gnomad EAS exome AF: 0.0000558

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.00121

Gnomad OTH exome AF: 0.00184

GnomAD4 exome AF: 0.000881 AC: 1286 AN: 1460318 Hom.: 0 Cov.: 33 AF XY: 0.000929 AC XY: 675 AN XY: 726420

African (AFR) AF: 0.000478 AC: 16 AN: 33466

American (AMR) AF: 0.00110 AC: 49 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00134 AC: 35 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000684 AC: 59 AN: 86242

European-Finnish (FIN) AF: 0.0000763 AC: 4 AN: 52412

Middle Eastern (MID) AF: 0.00555 AC: 32 AN: 5766

European-Non Finnish (NFE) AF: 0.000926 AC: 1029 AN: 1111554

Other (OTH) AF: 0.00103 AC: 62 AN: 60342

GnomAD4 genome AF: 0.000795 AC: 121 AN: 152266 Hom.: 2 Cov.: 32 AF XY: 0.000860 AC XY: 64 AN XY: 74442

African (AFR) AF: 0.000289 AC: 12 AN: 41538

American (AMR) AF: 0.000784 AC: 12 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00129 AC: 88 AN: 68020

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00107 Hom.: 0

Bravo AF: 0.000842

ESP6500AA AF: 0.000741 AC: 2

ESP6500EA AF: 0.000580 AC: 3

ExAC AF: 0.000873 AC: 105

EpiCase AF: 0.00218

EpiControl AF: 0.00172

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	-	Ehlers-Danlos syndrome due to tenascin-X deficiency (3)
-	1	2	not provided (3)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Ehlers-Danlos syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.021	T
MetaSVM	Benign	-1.1	T
PhyloP100		2.7
PrimateAI	Benign	0.32	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Benign	0.19
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.010	D
Vest4		0.099
MVP		0.26
ClinPred		0.096	T
GERP RS		4.1
Varity_R		0.13
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs183760368; hg19: chr6-32024650;