6-32096944-G-C

Variant names:

• chr6-32096944-G-C
• rs111244635
• NM_001365276.2:c.909C>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001365276.2(TNXB):​c.909C>G​(p.Gly303Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0025 in 1,593,688 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G303G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0056 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (11 hom.)
• Consequence: TNXB NM_001365276.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.82
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 6-32096944-G-C is Benign according to our data. Variant chr6-32096944-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261175.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.82 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00562 (848/151022) while in subpopulation AFR AF = 0.0162 (664/41096). AF 95% confidence interval is 0.0151. There are 7 homozygotes in GnomAd4. There are 386 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR,AD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNXB	NM_001365276.2	MANE Select	c.909C>G	p.Gly303Gly	synonymous	Exon 3 of 44	NP_001352205.1
	TNXB	NM_001428335.1		c.909C>G	p.Gly303Gly	synonymous	Exon 3 of 45	NP_001415264.1
	TNXB	NM_019105.8		c.909C>G	p.Gly303Gly	synonymous	Exon 3 of 44	NP_061978.6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNXB	ENST00000644971.2	MANE Select	c.909C>G	p.Gly303Gly	synonymous	Exon 3 of 44	ENSP00000496448.1
	TNXB	ENST00000479795.1	TSL:1	c.909C>G	p.Gly303Gly	synonymous	Exon 3 of 5	ENSP00000418248.1
	TNXB	ENST00000486148.1	TSL:1	n.1304C>G		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.00559 AC: 843 AN: 150906 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.0161

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00382

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000191

Gnomad MID AF: 0.00325

Gnomad NFE AF: 0.00168

Gnomad OTH AF: 0.00435

GnomAD2 exomes AF: 0.00214 AC: 525 AN: 245798 AF XY: 0.00190

Gnomad AFR exome AF: 0.0171

Gnomad AMR exome AF: 0.00199

Gnomad ASJ exome AF: 0.000201

Gnomad EAS exome AF: 0.0000560

Gnomad FIN exome AF: 0.000281

Gnomad NFE exome AF: 0.00166

Gnomad OTH exome AF: 0.00134

GnomAD4 exome AF: 0.00218 AC: 3143 AN: 1442666 Hom.: 11 Cov.: 33 AF XY: 0.00211 AC XY: 1517 AN XY: 717712

African (AFR) AF: 0.0140 AC: 467 AN: 33362

American (AMR) AF: 0.00243 AC: 107 AN: 44088

Ashkenazi Jewish (ASJ) AF: 0.000155 AC: 4 AN: 25816

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39656

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85948

European-Finnish (FIN) AF: 0.000303 AC: 16 AN: 52776

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5764

European-Non Finnish (NFE) AF: 0.00220 AC: 2411 AN: 1095726

Other (OTH) AF: 0.00220 AC: 131 AN: 59530

GnomAD4 genome AF: 0.00562 AC: 848 AN: 151022 Hom.: 7 Cov.: 33 AF XY: 0.00523 AC XY: 386 AN XY: 73798

African (AFR) AF: 0.0162 AC: 664 AN: 41096

American (AMR) AF: 0.00381 AC: 58 AN: 15206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5106

South Asian (SAS) AF: 0.00 AC: 0 AN: 4732

European-Finnish (FIN) AF: 0.000191 AC: 2 AN: 10450

Middle Eastern (MID) AF: 0.00347 AC: 1 AN: 288

European-Non Finnish (NFE) AF: 0.00168 AC: 114 AN: 67696

Other (OTH) AF: 0.00431 AC: 9 AN: 2090

Alfa AF: 0.00212 Hom.: 1

Bravo AF: 0.00645

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Cardiovascular phenotype (1)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	Ehlers-Danlos syndrome due to tenascin-X deficiency;C4014831:Vesicoureteral reflux 8 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	2.6
DANN	Benign	0.74
PhyloP100		-1.8
Mutation Taster		=95/5	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: rs111244635; hg19: chr6-32064721;