rs61910712

Positions:

chr6-32084478-T-C

Variant summary

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

The NM_001365276.2(TNXB):c.3380A>G(p.Lys1127Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00316 in 1,608,148 control chromosomes in the GnomAD database, including 137 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 Benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 65 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 72 hom. )

Consequence

TNXB
NM_001365276.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.03

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=0.0039838552).

BP6

Variant 6-32084478-T-C is Benign according to our data. Variant chr6-32084478-T-C is described in ClinVar as [Benign]. Clinvar id is 261134.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32084478-T-C is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0548 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNXB	NM_001365276.2 linkuse as main transcript	c.3380A>G	p.Lys1127Arg	missense_variant	8/44	ENST00000644971.2	NP_001352205.1
TNXB	NM_019105.8 linkuse as main transcript	c.3380A>G	p.Lys1127Arg	missense_variant	8/44		NP_061978.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2 linkuse as main transcript	c.3380A>G	p.Lys1127Arg	missense_variant	8/44		NM_001365276.2	ENSP00000496448		P22105-3
TNXB	ENST00000647633.1 linkuse as main transcript	c.4121A>G	p.Lys1374Arg	missense_variant	9/45			ENSP00000497649	P1
TNXB	ENST00000375244.7 linkuse as main transcript	c.3380A>G	p.Lys1127Arg	missense_variant	8/44	5		ENSP00000364393		P22105-3

Frequencies

GnomAD3 genomes

AF:

0.0165

AC:

2510

AN:

152028

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0569

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00648

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.0177

GnomAD3 exomes

AF:

0.00399

AC:

974

AN:

244128

Hom.:

AF XY:

0.00326

AC XY:

436

AN XY:

133598

show subpopulations

Gnomad AFR exome

AF:

0.0566

Gnomad AMR exome

AF:

0.00311

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000725

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000182

Gnomad OTH exome

AF:

0.00234

GnomAD4 exome

AF:

0.00176

AC:

2568

AN:

1456002

Hom.:

Cov.:

AF XY:

0.00152

AC XY:

1102

AN XY:

724026

show subpopulations

Gnomad4 AFR exome

AF:

0.0597

Gnomad4 AMR exome

AF:

0.00333

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000586

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000685

Gnomad4 OTH exome

AF:

0.00442

GnomAD4 genome

AF:

0.0165

AC:

2510

AN:

152146

Hom.:

Cov.:

AF XY:

0.0162

AC XY:

1203

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.0567

Gnomad4 AMR

AF:

0.00648

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.0175

Alfa

AF:

0.00690

Hom.:

Bravo

AF:

0.0194

ESP6500AA

AF:

0.0516

AC:

137

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.00431

AC:

512

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Ehlers-Danlos syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 15, 2022

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2018

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 23, 2019

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

0.087

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.067

T;.;T;.

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.13

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.74

.;T;T;T

MetaRNN

Benign

0.0040

T;T;T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

0.99

N;N

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.5

.;.;N;.

REVEL

Benign

0.13

Sift

Benign

0.48

.;.;T;.

Sift4G

Benign

0.071

.;.;T;D

Vest4

0.30

MVP

0.23

ClinPred

0.017

GERP RS

3.1

Varity_R

0.075

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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