rs12524664

Variant names:

• chr6-32061654-G-A
• rs12524664
• NM_001365276.2:c.7235C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-32061654-G-A
• chr6-32061654-G-C

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.7235C>T​(p.Pro2412Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0674 in 1,612,568 control chromosomes in the GnomAD database, including 4,611 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P2412P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.098 (925 hom., cov: 31)
  • Exomes 𝑓: 0.064 (3686 hom.)
• Consequence: TNXB NM_001365276.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.30
• 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Illumina, PanelApp Australia, Orphanet
• 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=0.0017334223).
• BP6: Variant 6-32061654-G-A is Benign according to our data. Variant chr6-32061654-G-A is described in ClinVar as Benign. ClinVar VariationId is 261155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.158 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNXB	NM_001365276.2	c.7235C>T	p.Pro2412Leu	missense_variant	Exon 21 of 44	ENST00000644971.2	NP_001352205.1
TNXB	NM_001428335.1	c.7976C>T	p.Pro2659Leu	missense_variant	Exon 22 of 45		NP_001415264.1
TNXB	NM_019105.8	c.7235C>T	p.Pro2412Leu	missense_variant	Exon 21 of 44		NP_061978.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2	c.7235C>T	p.Pro2412Leu	missense_variant	Exon 21 of 44		NM_001365276.2	ENSP00000496448.1
TNXB	ENST00000647633.1	c.7976C>T	p.Pro2659Leu	missense_variant	Exon 22 of 45			ENSP00000497649.1
TNXB	ENST00000375244.7	c.7235C>T	p.Pro2412Leu	missense_variant	Exon 21 of 44	5		ENSP00000364393.3

Frequencies

GnomAD3 genomes AF: 0.0979 AC: 14871 AN: 151950 Hom.: 923 Cov.: 31

Gnomad AFR AF: 0.162

Gnomad AMI AF: 0.0943

Gnomad AMR AF: 0.0720

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.0834

Gnomad SAS AF: 0.0386

Gnomad FIN AF: 0.175

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0631

Gnomad OTH AF: 0.0856

GnomAD2 exomes AF: 0.0780 AC: 19077 AN: 244426 AF XY: 0.0728

Gnomad AFR exome AF: 0.167

Gnomad AMR exome AF: 0.0927

Gnomad ASJ exome AF: 0.00957

Gnomad EAS exome AF: 0.0891

Gnomad FIN exome AF: 0.165

Gnomad NFE exome AF: 0.0625

Gnomad OTH exome AF: 0.0652

GnomAD4 exome AF: 0.0642 AC: 93775 AN: 1460500 Hom.: 3686 Cov.: 36 AF XY: 0.0626 AC XY: 45516 AN XY: 726544

African (AFR) AF: 0.163 AC: 5469 AN: 33480

American (AMR) AF: 0.0851 AC: 3808 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0108 AC: 281 AN: 26134

East Asian (EAS) AF: 0.0719 AC: 2854 AN: 39700

South Asian (SAS) AF: 0.0335 AC: 2893 AN: 86254

European-Finnish (FIN) AF: 0.159 AC: 8311 AN: 52272

Middle Eastern (MID) AF: 0.0429 AC: 247 AN: 5760

European-Non Finnish (NFE) AF: 0.0597 AC: 66355 AN: 1111830

Other (OTH) AF: 0.0589 AC: 3557 AN: 60346

GnomAD4 genome AF: 0.0978 AC: 14878 AN: 152068 Hom.: 925 Cov.: 31 AF XY: 0.100 AC XY: 7435 AN XY: 74340

African (AFR) AF: 0.162 AC: 6702 AN: 41456

American (AMR) AF: 0.0717 AC: 1096 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0107 AC: 37 AN: 3472

East Asian (EAS) AF: 0.0830 AC: 428 AN: 5154

South Asian (SAS) AF: 0.0394 AC: 190 AN: 4820

European-Finnish (FIN) AF: 0.175 AC: 1853 AN: 10580

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

European-Non Finnish (NFE) AF: 0.0631 AC: 4292 AN: 67986

Other (OTH) AF: 0.0851 AC: 180 AN: 2114

Alfa AF: 0.0539 Hom.: 170

Bravo AF: 0.0948

TwinsUK AF: 0.0572 AC: 212

ALSPAC AF: 0.0612 AC: 236

ESP6500AA AF: 0.164 AC: 367

ESP6500EA AF: 0.0629 AC: 312

ExAC AF: 0.0775 AC: 9168

Asia WGS AF: 0.0470 AC: 164 AN: 3478

EpiCase AF: 0.0642

EpiControl AF: 0.0618

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Dec 24, 2018

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.35	T;.;T;T
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.78	.;T;T;T
MetaRNN	Benign	0.0017	T;T;T;T
MetaSVM	Uncertain	0.10	D
PhyloP100		3.3
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-5.2	.;.;D;.
REVEL	Uncertain	0.30
Sift	Uncertain	0.0020	.;.;D;.
Sift4G	Uncertain	0.0040	.;.;D;D
Vest4		0.15
ClinPred		0.060	T
GERP RS		4.0
Varity_R		0.23
Mutation Taster		=94/6	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: rs12524664; hg19: chr6-32029431;