Genetic Variant NM_001365276.2:c.12210+39dupA (chr6-32042415-C-CT) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_001365276.2(TNXB):c.12210+39dupA variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 20)

Exomes 𝑓: 0.0015 ( 976 hom. )

Failed GnomAD Quality Control

Consequence

TNXB
NM_001365276.2 intron

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -3.69

Publications

0 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Illumina, PanelApp Australia, Orphanet
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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP6

Variant 6-32042415-C-CT is Benign according to our data. Variant chr6-32042415-C-CT is described in ClinVar as Likely_benign. ClinVar VariationId is 261121.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
TNXB	NM_001365276.2 link	c.12210+39dupA	intron_variant	Intron 40 of 43	ENST00000644971.2	NP_001352205.1
TNXB	NM_001428335.1 link	c.12951+39dupA	intron_variant	Intron 41 of 44		NP_001415264.1
TNXB	NM_019105.8 link	c.12204+39dupA	intron_variant	Intron 40 of 43		NP_061978.6	P22105-1O95680Q9Y464O95681
TNXB	NM_032470.4 link	c.1497+39dupA	intron_variant	Intron 9 of 12		NP_115859.2	P22105-2Q6IPK3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2 link	c.12210+39_12210+40insA		intron_variant	Intron 40 of 43		NM_001365276.2	ENSP00000496448.1		P22105-3

Frequencies

GnomAD3 genomes

AF:

0.00141

AC:

191

AN:

135452

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00313

Gnomad AMI

AF:

0.00246

Gnomad AMR

AF:

0.00161

Gnomad ASJ

AF:

0.000620

Gnomad EAS

AF:

0.000625

Gnomad SAS

AF:

0.00197

Gnomad FIN

AF:

0.0000990

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000716

Gnomad OTH

AF:

0.00161

GnomAD2 exomes

AF:

0.0000731

AC:

AN:

246348

AF XY:

0.000120

show subpopulations

Gnomad AFR exome

AF:

0.000264

Gnomad AMR exome

AF:

0.0000583

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000627

Gnomad OTH exome

AF:

0.000331

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00147

AC:

2070

AN:

1405160

Hom.:

976

Cov.:

AF XY:

0.00184

AC XY:

1286

AN XY:

699232

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00613

AC:

182

AN:

29702

American (AMR)

AF:

0.00175

AC:

AN:

44102

Ashkenazi Jewish (ASJ)

AF:

0.00229

AC:

AN:

25354

East Asian (EAS)

AF:

0.000773

AC:

AN:

38792

South Asian (SAS)

AF:

0.0113

AC:

898

AN:

79764

European-Finnish (FIN)

AF:

0.000438

AC:

AN:

52502

Middle Eastern (MID)

AF:

0.00143

AC:

AN:

5592

European-Non Finnish (NFE)

AF:

0.000672

AC:

720

AN:

1071368

Other (OTH)

AF:

0.00128

AC:

AN:

57984

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000000000826006), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.347

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00141

AC:

191

AN:

135568

Hom.:

Cov.:

AF XY:

0.00151

AC XY:

100

AN XY:

66076

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00312

AC:

104

AN:

33304

American (AMR)

AF:

0.00161

AC:

AN:

14274

Ashkenazi Jewish (ASJ)

AF:

0.000620

AC:

AN:

3228

East Asian (EAS)

AF:

0.000627

AC:

AN:

4788

South Asian (SAS)

AF:

0.00197

AC:

AN:

4068

European-Finnish (FIN)

AF:

0.0000990

AC:

AN:

10100

Middle Eastern (MID)

AF:

0.00

AC:

AN:

264

European-Non Finnish (NFE)

AF:

0.000716

AC:

AN:

62850

Other (OTH)

AF:

0.00160

AC:

AN:

1878

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.257

Heterozygous variant carriers

123

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000325

Hom.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-3.7

BranchPoint Hunter

1.0

Mutation Taster

=100/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over