6-32089365-G-A

Variant names:

• chr6-32089365-G-A
• rs112581362
• NM_001365276.2:c.2373C>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.2373C>T​(p.Ser791Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00248 in 1,606,748 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0056 (7 hom., cov: 32)
  • 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: 0.737
• 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: 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=-0.5).
• BP6: Variant 6-32089365-G-A is Benign according to our data. Variant chr6-32089365-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.737 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00561 (855/152346) while in subpopulation AFR AF = 0.0161 (670/41584). AF 95% confidence interval is 0.0151. There are 7 homozygotes in GnomAd4. There are 388 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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.2373C>T	p.Ser791Ser	synonymous	Exon 5 of 44	NP_001352205.1	P22105-3
	TNXB	NM_001428335.1		c.2373C>T	p.Ser791Ser	synonymous	Exon 5 of 45	NP_001415264.1	A0A3B3ISX9
	TNXB	NM_019105.8		c.2373C>T	p.Ser791Ser	synonymous	Exon 5 of 44	NP_061978.6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNXB	ENST00000644971.2	MANE Select	c.2373C>T	p.Ser791Ser	synonymous	Exon 5 of 44	ENSP00000496448.1	P22105-3
	TNXB	ENST00000647633.1		c.2373C>T	p.Ser791Ser	synonymous	Exon 5 of 45	ENSP00000497649.1	A0A3B3ISX9
	TNXB	ENST00000375244.7	TSL:5	c.2373C>T	p.Ser791Ser	synonymous	Exon 5 of 44	ENSP00000364393.3	P22105-3

Frequencies

GnomAD3 genomes AF: 0.00558 AC: 850 AN: 152228 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0160

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00168

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00214 AC: 523 AN: 244204 AF XY: 0.00189

Gnomad AFR exome AF: 0.0172

Gnomad AMR exome AF: 0.00197

Gnomad ASJ exome AF: 0.000201

Gnomad EAS exome AF: 0.0000563

Gnomad FIN exome AF: 0.000239

Gnomad NFE exome AF: 0.00166

Gnomad OTH exome AF: 0.00135

GnomAD4 exome AF: 0.00216 AC: 3136 AN: 1454402 Hom.: 11 Cov.: 32 AF XY: 0.00209 AC XY: 1509 AN XY: 722980

African (AFR) AF: 0.0138 AC: 463 AN: 33450

American (AMR) AF: 0.00241 AC: 107 AN: 44358

Ashkenazi Jewish (ASJ) AF: 0.000154 AC: 4 AN: 25986

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39650

South Asian (SAS) AF: 0.0000236 AC: 2 AN: 84600

European-Finnish (FIN) AF: 0.000315 AC: 16 AN: 50728

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5766

European-Non Finnish (NFE) AF: 0.00217 AC: 2408 AN: 1109710

Other (OTH) AF: 0.00216 AC: 130 AN: 60154

GnomAD4 genome AF: 0.00561 AC: 855 AN: 152346 Hom.: 7 Cov.: 32 AF XY: 0.00521 AC XY: 388 AN XY: 74498

African (AFR) AF: 0.0161 AC: 670 AN: 41584

American (AMR) AF: 0.00385 AC: 59 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00168 AC: 114 AN: 68024

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.00241 Hom.: 1

Bravo AF: 0.00644

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

ClinVar submissions

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	-0.50
CADD	Benign	7.2
DANN	Benign	0.70
PhyloP100		0.74
Mutation Taster		=99/1	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: rs112581362; hg19: chr6-32057142;