rs41270458

Variant names:

• chr6-32096119-G-A
• rs41270458
• NM_001365276.2:c.1734C>T

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.1734C>T​(p.Asp578Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0217 in 1,604,102 control chromosomes in the GnomAD database, including 444 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (36 hom., cov: 34)
  • Exomes 𝑓: 0.022 (408 hom.)
• Consequence: TNXB NM_001365276.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.78
• Publications: 8 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: Orphanet, Labcorp Genetics (formerly Invitae), Illumina, Genomics England PanelApp, PanelApp Australia
• 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=-0.85).
• BP6: Variant 6-32096119-G-A is Benign according to our data. Variant chr6-32096119-G-A is described in ClinVar as Benign. ClinVar VariationId is 261126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.78 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0183 (2782/151800) while in subpopulation NFE AF = 0.0255 (1730/67866). AF 95% confidence interval is 0.0245. There are 36 homozygotes in GnomAd4. There are 1374 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 36 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.1734C>T	p.Asp578Asp	synonymous	Exon 3 of 44	NP_001352205.1	P22105-3
	TNXB	NM_001428335.1		c.1734C>T	p.Asp578Asp	synonymous	Exon 3 of 45	NP_001415264.1	A0A3B3ISX9
	TNXB	NM_019105.8		c.1734C>T	p.Asp578Asp	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.1734C>T	p.Asp578Asp	synonymous	Exon 3 of 44	ENSP00000496448.1	P22105-3
	TNXB	ENST00000479795.1	TSL:1	c.1734C>T	p.Asp578Asp	synonymous	Exon 3 of 5	ENSP00000418248.1	C9J7W4
	TNXB	ENST00000486148.1	TSL:1	n.2129C>T		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.0183 AC: 2783 AN: 151680 Hom.: 36 Cov.: 34

Gnomad AFR AF: 0.00366

Gnomad AMI AF: 0.00444

Gnomad AMR AF: 0.0216

Gnomad ASJ AF: 0.00980

Gnomad EAS AF: 0.00390

Gnomad SAS AF: 0.0214

Gnomad FIN AF: 0.0334

Gnomad MID AF: 0.0132

Gnomad NFE AF: 0.0255

Gnomad OTH AF: 0.0264

GnomAD2 exomes AF: 0.0222 AC: 4974 AN: 224438 AF XY: 0.0236

Gnomad AFR exome AF: 0.00365

Gnomad AMR exome AF: 0.0150

Gnomad ASJ exome AF: 0.00856

Gnomad EAS exome AF: 0.00463

Gnomad FIN exome AF: 0.0345

Gnomad NFE exome AF: 0.0278

Gnomad OTH exome AF: 0.0210

GnomAD4 exome AF: 0.0221 AC: 32079 AN: 1452302 Hom.: 408 Cov.: 33 AF XY: 0.0225 AC XY: 16242 AN XY: 721586

African (AFR) AF: 0.00292 AC: 97 AN: 33242

American (AMR) AF: 0.0149 AC: 646 AN: 43426

Ashkenazi Jewish (ASJ) AF: 0.00798 AC: 206 AN: 25804

East Asian (EAS) AF: 0.00494 AC: 194 AN: 39264

South Asian (SAS) AF: 0.0253 AC: 2137 AN: 84506

European-Finnish (FIN) AF: 0.0347 AC: 1791 AN: 51624

Middle Eastern (MID) AF: 0.0135 AC: 78 AN: 5758

European-Non Finnish (NFE) AF: 0.0232 AC: 25672 AN: 1108614

Other (OTH) AF: 0.0209 AC: 1258 AN: 60064

GnomAD4 genome AF: 0.0183 AC: 2782 AN: 151800 Hom.: 36 Cov.: 34 AF XY: 0.0185 AC XY: 1374 AN XY: 74192

African (AFR) AF: 0.00364 AC: 151 AN: 41430

American (AMR) AF: 0.0216 AC: 329 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00980 AC: 34 AN: 3468

East Asian (EAS) AF: 0.00392 AC: 20 AN: 5108

South Asian (SAS) AF: 0.0213 AC: 102 AN: 4798

European-Finnish (FIN) AF: 0.0334 AC: 353 AN: 10576

Middle Eastern (MID) AF: 0.0142 AC: 4 AN: 282

European-Non Finnish (NFE) AF: 0.0255 AC: 1730 AN: 67866

Other (OTH) AF: 0.0261 AC: 55 AN: 2106

Alfa AF: 0.0229 Hom.: 111

Bravo AF: 0.0163

Asia WGS AF: 0.00808 AC: 28 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Cardiovascular phenotype (1)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.80
DANN	Benign	0.80
PhyloP100		-3.8
Mutation Taster		=98/2	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: rs41270458; hg19: chr6-32063896;