dbSNP rs149995364: TNXB:p.Gly1140Asp (chr6-32084439-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001365276.2(TNXB):c.3419G>A(p.Gly1140Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0114 in 1,595,588 control chromosomes in the GnomAD database, including 307 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 35 hom., cov: 32)

Exomes 𝑓: 0.011 ( 272 hom. )

Consequence

TNXB
NM_001365276.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.95

Publications

7 publications found

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 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: Orphanet, Labcorp Genetics (formerly Invitae), Illumina, Genomics England PanelApp, PanelApp Australia
familial vesicoureteral reflux
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
vesicoureteral reflux 8
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

TNXB links:

ENSG00000294466 (HGNC:):

ENSG00000294466 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0024562776).

BP6

Variant 6-32084439-C-T is Benign according to our data. Variant chr6-32084439-C-T is described in ClinVar as Benign. ClinVar VariationId is 261135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0128 (1949/152330) while in subpopulation AMR AF = 0.036 (551/15302). AF 95% confidence interval is 0.0335. There are 35 homozygotes in GnomAd4. There are 879 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 35 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365276.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TNXB	NM_001365276.2	MANE Select	c.3419G>A	p.Gly1140Asp	missense	Exon 8 of 44	NP_001352205.1	P22105-3
TNXB	NM_001428335.1		c.4160G>A	p.Gly1387Asp	missense	Exon 9 of 45	NP_001415264.1	A0A3B3ISX9
TNXB	NM_019105.8		c.3419G>A	p.Gly1140Asp	missense	Exon 8 of 44	NP_061978.6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TNXB	ENST00000644971.2	MANE Select	c.3419G>A	p.Gly1140Asp	missense	Exon 8 of 44	ENSP00000496448.1	P22105-3
TNXB	ENST00000647633.1		c.4160G>A	p.Gly1387Asp	missense	Exon 9 of 45	ENSP00000497649.1	A0A3B3ISX9
TNXB	ENST00000375244.7	TSL:5	c.3419G>A	p.Gly1140Asp	missense	Exon 8 of 44	ENSP00000364393.3	P22105-3

Frequencies

GnomAD3 genomes

AF:

0.0128

AC:

1946

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00540

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0360

Gnomad ASJ

AF:

0.100

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.000753

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0107

Gnomad OTH

AF:

0.0354

GnomAD2 exomes

AF:

0.0158

AC:

3840

AN:

242786

AF XY:

0.0143

show subpopulations

Gnomad AFR exome

AF:

0.00537

Gnomad AMR exome

AF:

0.0358

Gnomad ASJ exome

AF:

0.0991

Gnomad EAS exome

AF:

0.0000560

Gnomad FIN exome

AF:

0.00159

Gnomad NFE exome

AF:

0.0119

Gnomad OTH exome

AF:

0.0300

GnomAD4 exome

AF:

0.0112

AC:

16188

AN:

1443258

Hom.:

272

Cov.:

AF XY:

0.0110

AC XY:

7871

AN XY:

715014

show subpopulations

African (AFR)

AF:

0.00595

AC:

198

AN:

33296

American (AMR)

AF:

0.0362

AC:

1612

AN:

44542

Ashkenazi Jewish (ASJ)

AF:

0.0967

AC:

2499

AN:

25844

East Asian (EAS)

AF:

0.000152

AC:

AN:

39358

South Asian (SAS)

AF:

0.00177

AC:

150

AN:

84564

European-Finnish (FIN)

AF:

0.00140

AC:

AN:

49298

Middle Eastern (MID)

AF:

0.0290

AC:

166

AN:

5732

European-Non Finnish (NFE)

AF:

0.00941

AC:

10357

AN:

1100960

Other (OTH)

AF:

0.0190

AC:

1131

AN:

59664

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

835

1669

2504

3338

4173

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

422

844

1266

1688

2110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0128

AC:

1949

AN:

152330

Hom.:

Cov.:

AF XY:

0.0118

AC XY:

879

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.00541

AC:

225

AN:

41578

American (AMR)

AF:

0.0360

AC:

551

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.100

AC:

347

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.00166

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000753

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0107

AC:

727

AN:

68036

Other (OTH)

AF:

0.0351

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

101

202

302

403

504

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0139

Hom.:

135

Bravo

AF:

0.0165

TwinsUK

AF:

0.00890

AC:

ALSPAC

AF:

0.00960

AC:

ESP6500AA

AF:

0.00366

AC:

ESP6500EA

AF:

0.0128

AC:

ExAC

AF:

0.0133

AC:

1573

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0148

EpiControl

AF:

0.0162

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cardiovascular phenotype (1)

Ehlers-Danlos syndrome (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.37

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

Eigen

Uncertain

0.30

Eigen_PC

Benign

0.13

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.84

MetaRNN

Benign

0.0025

MetaSVM

Benign

-0.86

PhyloP100

1.9

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-4.2

REVEL

Benign

0.26

Sift

Benign

0.091

Sift4G

Uncertain

0.0070

Vest4

0.20

ClinPred

0.039

GERP RS

4.2

Varity_R

0.31

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over