rs116701346

Variant names:

• chr6-32046413-G-A
• rs116701346
• NM_001365276.2:c.10368C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-32046413-G-A
• chr6-32046413-G-C
• chr6-32046413-G-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_001428335.1(TNXB):​c.11109C>T​(p.Thr3703Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000719 in 1,579,948 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00053 (5 hom.)
• Consequence: TNXB NM_001428335.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -3.07
• 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=-0.77).
• BP6: Variant 6-32046413-G-A is Benign according to our data. Variant chr6-32046413-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.07 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.00053 (757/1427610) while in subpopulation AFR AF = 0.00915 (302/33002). AF 95% confidence interval is 0.0083. There are 5 homozygotes in GnomAdExome4. There are 364 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001428335.1. 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.10368C>T	p.Thr3456Thr	synonymous	Exon 31 of 44	NP_001352205.1
	TNXB	NM_001428335.1		c.11109C>T	p.Thr3703Thr	synonymous	Exon 32 of 45	NP_001415264.1
	TNXB	NM_019105.8		c.10362C>T	p.Thr3454Thr	synonymous	Exon 31 of 44	NP_061978.6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNXB	ENST00000644971.2	MANE Select	c.10368C>T	p.Thr3456Thr	synonymous	Exon 31 of 44	ENSP00000496448.1
	TNXB	ENST00000490077.5	TSL:1	n.195C>T		non_coding_transcript_exon	Exon 1 of 14
	TNXB	ENST00000647633.1		c.11109C>T	p.Thr3703Thr	synonymous	Exon 32 of 45	ENSP00000497649.1

Frequencies

GnomAD3 genomes AF: 0.00247 AC: 376 AN: 152220 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00743

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.000808 AC: 195 AN: 241284 AF XY: 0.000636

Gnomad AFR exome AF: 0.00591

Gnomad AMR exome AF: 0.000527

Gnomad ASJ exome AF: 0.000921

Gnomad EAS exome AF: 0.000168

Gnomad FIN exome AF: 0.00150

Gnomad NFE exome AF: 0.000408

Gnomad OTH exome AF: 0.000676

GnomAD4 exome AF: 0.000530 AC: 757 AN: 1427610 Hom.: 5 Cov.: 31 AF XY: 0.000517 AC XY: 364 AN XY: 703546

African (AFR) AF: 0.00915 AC: 302 AN: 33002

American (AMR) AF: 0.000543 AC: 24 AN: 44174

Ashkenazi Jewish (ASJ) AF: 0.00116 AC: 30 AN: 25762

East Asian (EAS) AF: 0.000180 AC: 7 AN: 38870

South Asian (SAS) AF: 0.0000834 AC: 7 AN: 83962

European-Finnish (FIN) AF: 0.00209 AC: 102 AN: 48688

Middle Eastern (MID) AF: 0.00176 AC: 10 AN: 5688

European-Non Finnish (NFE) AF: 0.000200 AC: 218 AN: 1088548

Other (OTH) AF: 0.000967 AC: 57 AN: 58916

GnomAD4 genome AF: 0.00249 AC: 379 AN: 152338 Hom.: 3 Cov.: 32 AF XY: 0.00239 AC XY: 178 AN XY: 74496

African (AFR) AF: 0.00748 AC: 311 AN: 41586

American (AMR) AF: 0.000784 AC: 12 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00226 AC: 24 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000397 AC: 27 AN: 68022

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.00146 Hom.: 0

Bravo AF: 0.00210

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000437

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.18
DANN	Benign	0.65
PhyloP100		-3.1
PromoterAI		0.066	Neutral
Mutation Taster		=100/0	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: rs116701346; hg19: chr6-32014190;