ENST00000451343.4:c.-37A>G

Variant names:

• chr6-32045256-T-C
• rs199757950
• ENST00000451343.4:c.-37A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The ENST00000451343.4(TNXB):​c.-37A>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0042 (0 hom., cov: 20)
  • Exomes 𝑓: 0.0052 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TNXB ENST00000451343.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0250
• Publications: 0 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 6-32045256-T-C is Benign according to our data. Variant chr6-32045256-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 261097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000451343.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNXB	NM_001365276.2	MANE Select	c.10677A>G	p.Leu3559Leu	synonymous	Exon 32 of 44	NP_001352205.1
	TNXB	NM_032470.4		c.-37A>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 13	NP_115859.2
	TNXB	NM_001428335.1		c.11418A>G	p.Leu3806Leu	synonymous	Exon 33 of 45	NP_001415264.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNXB	ENST00000451343.4	TSL:1	c.-37A>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 13	ENSP00000407685.1
	TNXB	ENST00000644971.2	MANE Select	c.10677A>G	p.Leu3559Leu	synonymous	Exon 32 of 44	ENSP00000496448.1
	TNXB	ENST00000451343.4	TSL:1	c.-37A>G		5_prime_UTR	Exon 1 of 13	ENSP00000407685.1

Frequencies

GnomAD3 genomes AF: 0.00422 AC: 630 AN: 149466 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.00178

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00493

Gnomad ASJ AF: 0.0124

Gnomad EAS AF: 0.00120

Gnomad SAS AF: 0.00830

Gnomad FIN AF: 0.000381

Gnomad MID AF: 0.0667

Gnomad NFE AF: 0.00518

Gnomad OTH AF: 0.0133

GnomAD2 exomes AF: 0.00564 AC: 1135 AN: 201068 AF XY: 0.00641

Gnomad AFR exome AF: 0.00198

Gnomad AMR exome AF: 0.00387

Gnomad ASJ exome AF: 0.0108

Gnomad EAS exome AF: 0.000375

Gnomad FIN exome AF: 0.000327

Gnomad NFE exome AF: 0.00583

Gnomad OTH exome AF: 0.00862

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00518 AC: 7455 AN: 1439300 Hom.: 0 Cov.: 31 AF XY: 0.00547 AC XY: 3909 AN XY: 714498

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

African (AFR) AF: 0.00190 AC: 63 AN: 33204

American (AMR) AF: 0.00383 AC: 168 AN: 43826

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 284 AN: 25436

East Asian (EAS) AF: 0.000456 AC: 18 AN: 39504

South Asian (SAS) AF: 0.0111 AC: 924 AN: 83520

European-Finnish (FIN) AF: 0.000655 AC: 34 AN: 51870

Middle Eastern (MID) AF: 0.0472 AC: 242 AN: 5126

European-Non Finnish (NFE) AF: 0.00484 AC: 5310 AN: 1097462

Other (OTH) AF: 0.00694 AC: 412 AN: 59352

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00417 AC: 624 AN: 149586 Hom.: 0 Cov.: 20 AF XY: 0.00425 AC XY: 310 AN XY: 72942

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

African (AFR) AF: 0.00178 AC: 73 AN: 41104

American (AMR) AF: 0.00493 AC: 74 AN: 15024

Ashkenazi Jewish (ASJ) AF: 0.0124 AC: 42 AN: 3382

East Asian (EAS) AF: 0.00120 AC: 6 AN: 5006

South Asian (SAS) AF: 0.00810 AC: 38 AN: 4694

European-Finnish (FIN) AF: 0.000381 AC: 4 AN: 10506

Middle Eastern (MID) AF: 0.0567 AC: 16 AN: 282

European-Non Finnish (NFE) AF: 0.00518 AC: 345 AN: 66632

Other (OTH) AF: 0.0127 AC: 26 AN: 2046

⚠️ 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.

Alfa AF: 0.00936 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	5.4
DANN	Benign	0.81
PhyloP100		-0.025
Mutation Taster		=300/0	polymorphism

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

Other links and lift over

dbSNP: rs199757950; hg19: chr6-32013033;