chr6-32044177-T-C

Variant names:

• chr6-32044177-T-C
• rs2856450
• NM_001365276.2:c.11264-48A>G

Variant summary

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

The NM_001365276.2(TNXB):​c.11264-48A>G variant causes a intron 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 0.11 (656 hom., cov: 18)
  • Exomes 𝑓: 0.093 (23017 hom.)
  • Failed GnomAD Quality Control
• Consequence: TNXB NM_001365276.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.07
• Publications: 1 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=-0.94).
• BP6: Variant 6-32044177-T-C is Benign according to our data. Variant chr6-32044177-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNXB	NM_001365276.2	MANE Select	c.11264-48A>G		intron	N/A	NP_001352205.1
	TNXB	NM_001428335.1		c.12005-48A>G		intron	N/A	NP_001415264.1
	TNXB	NM_019105.8		c.11258-48A>G		intron	N/A	NP_061978.6

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNXB	ENST00000644971.2	MANE Select	c.11264-48A>G		intron	N/A	ENSP00000496448.1
	TNXB	ENST00000451343.4	TSL:1	c.551-48A>G		intron	N/A	ENSP00000407685.1
	TNXB	ENST00000490077.5	TSL:1	n.1091-48A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.110 AC: 10082 AN: 91794 Hom.: 654 Cov.: 18

Gnomad AFR AF: 0.0952

Gnomad AMI AF: 0.0935

Gnomad AMR AF: 0.131

Gnomad ASJ AF: 0.110

Gnomad EAS AF: 0.165

Gnomad SAS AF: 0.173

Gnomad FIN AF: 0.136

Gnomad MID AF: 0.201

Gnomad NFE AF: 0.101

Gnomad OTH AF: 0.0920

GnomAD2 exomes AF: 0.0151 AC: 2728 AN: 180354 AF XY: 0.0147

Gnomad AFR exome AF: 0.00468

Gnomad AMR exome AF: 0.0104

Gnomad ASJ exome AF: 0.0146

Gnomad EAS exome AF: 0.0585

Gnomad FIN exome AF: 0.00625

Gnomad NFE exome AF: 0.00577

Gnomad OTH exome AF: 0.0162

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0931 AC: 99289 AN: 1066198 Hom.: 23017 Cov.: 31 AF XY: 0.0984 AC XY: 52088 AN XY: 529618

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

African (AFR) AF: 0.118 AC: 2836 AN: 23980

American (AMR) AF: 0.183 AC: 5326 AN: 29174

Ashkenazi Jewish (ASJ) AF: 0.166 AC: 3313 AN: 19962

East Asian (EAS) AF: 0.245 AC: 7169 AN: 29310

South Asian (SAS) AF: 0.195 AC: 11278 AN: 57722

European-Finnish (FIN) AF: 0.188 AC: 7246 AN: 38618

Middle Eastern (MID) AF: 0.162 AC: 536 AN: 3304

European-Non Finnish (NFE) AF: 0.0680 AC: 55815 AN: 820234

Other (OTH) AF: 0.131 AC: 5770 AN: 43894

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.110 AC: 10085 AN: 91830 Hom.: 656 Cov.: 18 AF XY: 0.108 AC XY: 4792 AN XY: 44482

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

African (AFR) AF: 0.0953 AC: 2249 AN: 23588

American (AMR) AF: 0.131 AC: 1239 AN: 9428

Ashkenazi Jewish (ASJ) AF: 0.110 AC: 250 AN: 2268

East Asian (EAS) AF: 0.164 AC: 539 AN: 3290

South Asian (SAS) AF: 0.172 AC: 459 AN: 2670

European-Finnish (FIN) AF: 0.136 AC: 822 AN: 6048

Middle Eastern (MID) AF: 0.210 AC: 44 AN: 210

European-Non Finnish (NFE) AF: 0.101 AC: 4317 AN: 42580

Other (OTH) AF: 0.0955 AC: 123 AN: 1288

⚠️ 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: 0.0601 Hom.: 209

ClinVar

ClinVar submissions as Germline

Significance: Benign/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	-0.94
CADD	Benign	9.9
DANN	Benign	0.35
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs2856450; hg19: chr6-32011954; COSMIC: COSV107499830; COSMIC: COSV107499830;