rs529527925

Positions:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_001365276.2(TNXB):c.10045G>C(p.Ala3349Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000128 in 1,474,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

TNXB
NM_001365276.2 missense, splice_region

Scores

Splicing: ADA: 0.9892

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.330

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 -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0061703026).

BP6

Variant 6-32048363-C-G is Benign according to our data. Variant chr6-32048363-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 1197407.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNXB	NM_001365276.2 linkuse as main transcript	c.10045G>C	p.Ala3349Pro	missense_variant, splice_region_variant	29/44	ENST00000644971.2	NP_001352205.1
TNXB	NM_019105.8 linkuse as main transcript	c.10039G>C	p.Ala3347Pro	missense_variant, splice_region_variant	29/44		NP_061978.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2 linkuse as main transcript	c.10045G>C	p.Ala3349Pro	missense_variant, splice_region_variant	29/44		NM_001365276.2	ENSP00000496448		P22105-3
TNXB	ENST00000647633.1 linkuse as main transcript	c.10786G>C	p.Ala3596Pro	missense_variant, splice_region_variant	30/45			ENSP00000497649	P1
TNXB	ENST00000375244.7 linkuse as main transcript	c.10045G>C	p.Ala3349Pro	missense_variant, splice_region_variant	29/44	5		ENSP00000364393		P22105-3

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00346

Gnomad SAS

AF:

0.00165

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000552

AC:

AN:

168606

Hom.:

AF XY:

0.000600

AC XY:

AN XY:

90034

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00565

Gnomad SAS exome

AF:

0.000553

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000526

GnomAD4 exome

AF:

0.000123

AC:

163

AN:

1322560

Hom.:

Cov.:

AF XY:

0.000137

AC XY:

AN XY:

643782

show subpopulations

Gnomad4 AFR exome

AF:

0.0000336

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00298

Gnomad4 SAS exome

AF:

0.000508

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000576

Gnomad4 OTH exome

AF:

0.000221

GnomAD4 genome

AF:

0.000171

AC:

AN:

152314

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00347

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000117

ExAC

AF:

0.000375

AC:

Asia WGS

AF:

0.00404

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 18, 2021	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	TNXB: BP4 -

TNXB-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 27, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 16, 2023

This alteration is classified as likely 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

0.15

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.60

CADD

Benign

5.3

DANN

Benign

0.87

DEOGEN2

Benign

0.031

.;.;.;T

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.030

LIST_S2

Benign

0.099

.;T;T;T

M_CAP

Benign

0.0049

MetaRNN

Benign

0.0062

T;T;T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.28

PROVEAN

Benign

-2.4

.;.;N;.

REVEL

Benign

0.086

Sift

Benign

0.038

.;.;D;.

Sift4G

Benign

0.20

.;.;T;T

Vest4

0.060

MVP

0.043

ClinPred

0.079

GERP RS

-1.8

Varity_R

0.22

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Benign

0.62

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

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