NM_001365276.2:c.7235C>T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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 (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.098 ( 925 hom., cov: 31)

Exomes 𝑓: 0.064 ( 3686 hom. )

Consequence

TNXB
NM_001365276.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 3.30

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 261155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32061654-G-A is described in Lovd as [Benign].

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 link	c.7235C>T	p.Pro2412Leu	missense_variant	Exon 21 of 44	ENST00000644971.2	NP_001352205.1
TNXB	NM_001428335.1 link	c.7976C>T	p.Pro2659Leu	missense_variant	Exon 22 of 45		NP_001415264.1
TNXB	NM_019105.8 link	c.7235C>T	p.Pro2412Leu	missense_variant	Exon 21 of 44		NP_061978.6	P22105-1O95680Q9Y464O95681

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TNXB	ENST00000644971.2 link	c.7235C>T	p.Pro2412Leu	missense_variant	Exon 21 of 44		NM_001365276.2	ENSP00000496448.1	P22105-3
TNXB	ENST00000647633.1 link	c.7976C>T	p.Pro2659Leu	missense_variant	Exon 22 of 45			ENSP00000497649.1	A0A3B3ISX9
TNXB	ENST00000375244.7 link	c.7235C>T	p.Pro2412Leu	missense_variant	Exon 21 of 44	5		ENSP00000364393.3	P22105-3

Frequencies

GnomAD3 genomes

AF:

0.0979

AC:

14871

AN:

151950

Hom.:

923

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0780

AC:

19077

AN:

244426

Hom.:

1047

AF XY:

0.0728

AC XY:

9734

AN XY:

133666

show subpopulations

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 SAS exome

AF:

0.0323

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.:

AF XY:

0.0626

AC XY:

45516

AN XY:

726544

show subpopulations

Gnomad4 AFR exome

AF:

0.163

Gnomad4 AMR exome

AF:

0.0851

Gnomad4 ASJ exome

AF:

0.0108

Gnomad4 EAS exome

AF:

0.0719

Gnomad4 SAS exome

AF:

0.0335

Gnomad4 FIN exome

AF:

0.159

Gnomad4 NFE exome

AF:

0.0597

Gnomad4 OTH exome

AF:

0.0589

GnomAD4 genome

AF:

0.0978

AC:

14878

AN:

152068

Hom.:

925

Cov.:

AF XY:

0.100

AC XY:

7435

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.162

Gnomad4 AMR

AF:

0.0717

Gnomad4 ASJ

AF:

0.0107

Gnomad4 EAS

AF:

0.0830

Gnomad4 SAS

AF:

0.0394

Gnomad4 FIN

AF:

0.175

Gnomad4 NFE

AF:

0.0631

Gnomad4 OTH

AF:

0.0851

Alfa

AF:

0.0526

Hom.:

158

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

LINK: link

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

BayesDel_noAF

Benign

-0.37

CADD

Uncertain

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

LIST_S2

Benign

0.78

.;T;T;T

MetaRNN

Benign

0.0017

T;T;T;T

MetaSVM

Uncertain

0.10

PrimateAI

Benign

0.43

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

GERP RS

4.0

Varity_R

0.23

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over