rs204885

Positions:

• chr6-32062152-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BA1

The NM_001365276.2(TNXB):​c.7168+5G>A variant causes a splice donor 5th base, intron change. The variant allele was found at a frequency of 0.0364 in 1,609,336 control chromosomes in the GnomAD database, including 1,339 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (189 hom., cov: 32)
  • Exomes 𝑓: 0.036 (1150 hom.)
• Consequence: TNXB NM_001365276.2 splice_donor_5th_base, intron
• Scores: Splicing: ADA: 0.9956
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.37

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 6-32062152-C-T is Benign according to our data. Variant chr6-32062152-C-T is described in ClinVar as [Benign]. Clinvar id is 261154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32062152-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0782 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNXB	NM_001365276.2	c.7168+5G>A		splice_donor_5th_base_variant, intron_variant		ENST00000644971.2
TNXB	NM_019105.8	c.7168+5G>A		splice_donor_5th_base_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNXB	ENST00000644971.2	c.7168+5G>A		splice_donor_5th_base_variant, intron_variant			NM_001365276.2
TNXB	ENST00000375244.7	c.7168+5G>A		splice_donor_5th_base_variant, intron_variant		5
TNXB	ENST00000647633.1	c.7909+5G>A		splice_donor_5th_base_variant, intron_variant				P1

Frequencies

GnomAD3 genomes AF: 0.0432 AC: 6579 AN: 152232 Hom.: 190 Cov.: 32

Gnomad AFR AF: 0.0806

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.0480

Gnomad ASJ AF: 0.0147

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00263

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0337

Gnomad OTH AF: 0.0454

GnomAD3 exomes AF: 0.0251 AC: 6118 AN: 243866 Hom.: 129 AF XY: 0.0233 AC XY: 3099 AN XY: 133024

Gnomad AFR exome AF: 0.0808

Gnomad AMR exome AF: 0.0337

Gnomad ASJ exome AF: 0.0129

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000297

Gnomad FIN exome AF: 0.00369

Gnomad NFE exome AF: 0.0308

Gnomad OTH exome AF: 0.0333

GnomAD4 exome AF: 0.0357 AC: 52050 AN: 1456986 Hom.: 1150 Cov.: 33 AF XY: 0.0338 AC XY: 24476 AN XY: 724008

Gnomad4 AFR exome AF: 0.0794

Gnomad4 AMR exome AF: 0.0356

Gnomad4 ASJ exome AF: 0.0142

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.000291

Gnomad4 FIN exome AF: 0.00429

Gnomad4 NFE exome AF: 0.0407

Gnomad4 OTH exome AF: 0.0338

GnomAD4 genome AF: 0.0432 AC: 6585 AN: 152350 Hom.: 189 Cov.: 32 AF XY: 0.0408 AC XY: 3042 AN XY: 74498

Gnomad4 AFR AF: 0.0805

Gnomad4 AMR AF: 0.0480

Gnomad4 ASJ AF: 0.0147

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00263

Gnomad4 NFE AF: 0.0337

Gnomad4 OTH AF: 0.0449

Alfa AF: 0.0364 Hom.: 62

Bravo AF: 0.0497

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.0335

EpiControl AF: 0.0332

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

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

Jul 14, 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

Dec 21, 2018

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
BayesDel_noAF	Benign	-0.38
CADD	Benign	21
DANN	Benign	0.86

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.83
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

Other links and lift over

dbSNP: rs204885; hg19: chr6-32029929;