6-32064851-C-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001365276.2(TNXB):c.6811G>C(p.Val2271Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00523 in 1,611,140 control chromosomes in the GnomAD database, including 106 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0049 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0053 ( 102 hom. )

Consequence

TNXB
NM_001365276.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -2.25

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=0.004063517).

BP6

Variant 6-32064851-C-G is Benign according to our data. Variant chr6-32064851-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 261151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32064851-C-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00486 (740/152332) while in subpopulation EAS AF= 0.0135 (70/5180). AF 95% confidence interval is 0.011. There are 4 homozygotes in gnomad4. There are 399 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNXB	NM_001365276.2 link	c.6811G>C	p.Val2271Leu	missense_variant	Exon 19 of 44	ENST00000644971.2	NP_001352205.1
TNXB	NM_001428335.1 link	c.7552G>C	p.Val2518Leu	missense_variant	Exon 20 of 45		NP_001415264.1
TNXB	NM_019105.8 link	c.6811G>C	p.Val2271Leu	missense_variant	Exon 19 of 44		NP_061978.6	P22105-1O95680Q9Y464O95681

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TNXB	ENST00000644971.2 link	c.6811G>C	p.Val2271Leu	missense_variant	Exon 19 of 44		NM_001365276.2	ENSP00000496448.1	P22105-3
TNXB	ENST00000647633.1 link	c.7552G>C	p.Val2518Leu	missense_variant	Exon 20 of 45			ENSP00000497649.1	A0A3B3ISX9
TNXB	ENST00000375244.7 link	c.6811G>C	p.Val2271Leu	missense_variant	Exon 19 of 44	5		ENSP00000364393.3	P22105-3

Frequencies

GnomAD3 genomes

AF:

0.00487

AC:

741

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00152

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00661

Gnomad ASJ

AF:

0.0251

Gnomad EAS

AF:

0.0135

Gnomad SAS

AF:

0.0135

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00485

Gnomad OTH

AF:

0.00669

GnomAD3 exomes

AF:

0.00653

AC:

1591

AN:

243792

Hom.:

AF XY:

0.00731

AC XY:

976

AN XY:

133472

show subpopulations

Gnomad AFR exome

AF:

0.000628

Gnomad AMR exome

AF:

0.00448

Gnomad ASJ exome

AF:

0.0283

Gnomad EAS exome

AF:

0.0115

Gnomad SAS exome

AF:

0.0122

Gnomad FIN exome

AF:

0.000511

Gnomad NFE exome

AF:

0.00453

Gnomad OTH exome

AF:

0.0110

GnomAD4 exome

AF:

0.00526

AC:

7680

AN:

1458808

Hom.:

102

Cov.:

AF XY:

0.00568

AC XY:

4119

AN XY:

725718

show subpopulations

Gnomad4 AFR exome

AF:

0.00206

Gnomad4 AMR exome

AF:

0.00481

Gnomad4 ASJ exome

AF:

0.0296

Gnomad4 EAS exome

AF:

0.0400

Gnomad4 SAS exome

AF:

0.0119

Gnomad4 FIN exome

AF:

0.000710

Gnomad4 NFE exome

AF:

0.00311

Gnomad4 OTH exome

AF:

0.00652

GnomAD4 genome

AF:

0.00486

AC:

740

AN:

152332

Hom.:

Cov.:

AF XY:

0.00536

AC XY:

399

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.00149

Gnomad4 AMR

AF:

0.00660

Gnomad4 ASJ

AF:

0.0251

Gnomad4 EAS

AF:

0.0135

Gnomad4 SAS

AF:

0.0135

Gnomad4 FIN

AF:

0.000471

Gnomad4 NFE

AF:

0.00485

Gnomad4 OTH

AF:

0.00662

Alfa

AF:

0.00708

Hom.:

Bravo

AF:

0.00521

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000797

AC:

ESP6500EA

AF:

0.00588

AC:

ExAC

AF:

0.00622

AC:

736

Asia WGS

AF:

0.0110

AC:

AN:

3478

EpiCase

AF:

0.00649

EpiControl

AF:

0.00747

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 24, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TNXB: BP4, BS1, BS2 -

Jul 19, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ehlers-Danlos syndrome

Benign:1

Feb 08, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Benign:1

Feb 12, 2019

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

0.16

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.0040

DANN

Benign

0.81

DEOGEN2

Benign

0.034

T;.;T

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0035

LIST_S2

Benign

0.077

.;T;T

MetaRNN

Benign

0.0041

T;T;T

MetaSVM

Benign

-0.91

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.89

.;.;N

REVEL

Benign

0.025

Sift

Benign

0.30

.;.;T

Sift4G

Benign

0.28

.;.;T

Vest4

0.057

MVP

0.12

ClinPred

0.0038

GERP RS

-8.3

Varity_R

0.070

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