rs199828189

chr6-32049596-GAGA-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001365276.2(TNXB):c.9440-12_9440-10del variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00484 in 1,607,978 control chromosomes in the GnomAD database, including 160 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0055 (22 hom., cov: 32)
  • Exomes 𝑓: 0.0048 (138 hom.)
• Consequence: TNXB NM_001365276.2 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.249

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 -16 ACMG points.

• BP6: Variant 6-32049596-GAGA-G is Benign according to our data. Variant chr6-32049596-GAGA-G is described in ClinVar as [Benign]. Clinvar id is 261176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32049596-GAGA-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00554 (843/152252) while in subpopulation AMR AF= 0.031 (474/15304). AF 95% confidence interval is 0.0287. There are 22 homozygotes in gnomad4. There are 480 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 21 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNXB	NM_001365276.2	c.9440-12_9440-10del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000644971.2
TNXB	NM_019105.8	c.9434-12_9434-10del		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNXB	ENST00000644971.2	c.9440-12_9440-10del		splice_polypyrimidine_tract_variant, intron_variant			NM_001365276.2
TNXB	ENST00000375244.7	c.9440-12_9440-10del		splice_polypyrimidine_tract_variant, intron_variant		5
TNXB	ENST00000647633.1	c.10181-12_10181-10del		splice_polypyrimidine_tract_variant, intron_variant				P1

Frequencies

GnomAD3 genomes AF: 0.00550 AC: 837 AN: 152134 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0306

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0208

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00246

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.0103 AC: 2483 AN: 241676 Hom.: 71 AF XY: 0.00785 AC XY: 1040 AN XY: 132438

Gnomad AFR exome AF: 0.000422

Gnomad AMR exome AF: 0.0513

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0174

Gnomad SAS exome AF: 0.000330

Gnomad FIN exome AF: 0.00783

Gnomad NFE exome AF: 0.00190

Gnomad OTH exome AF: 0.00538

GnomAD4 exome AF: 0.00476 AC: 6936 AN: 1455726 Hom.: 138 AF XY: 0.00436 AC XY: 3152 AN XY: 723404

Gnomad4 AFR exome AF: 0.000480

Gnomad4 AMR exome AF: 0.0454

Gnomad4 ASJ exome AF: 0.0000769

Gnomad4 EAS exome AF: 0.0413

Gnomad4 SAS exome AF: 0.000325

Gnomad4 FIN exome AF: 0.00761

Gnomad4 NFE exome AF: 0.00241

Gnomad4 OTH exome AF: 0.00283

GnomAD4 genome AF: 0.00554 AC: 843 AN: 152252 Hom.: 22 Cov.: 32 AF XY: 0.00645 AC XY: 480 AN XY: 74442

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.0310

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0209

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00659

Gnomad4 NFE AF: 0.00246

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00284 Hom.: 1

Bravo AF: 0.00685

Asia WGS AF: 0.00924 AC: 33 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

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 22, 2022

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 14, 2018

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.36		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.36		Position offset: 39

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs199828189; hg19: chr6-32017373;