rs373531814

Variant names:

• chr6-32049635-C-A
• rs373531814
• NM_001365276.2:c.9440-48G>T

Your query was ambiguous. Multiple possible variants found:

• chr6-32049635-C-A
• chr6-32049635-C-G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The ENST00000644971.2(TNXB):​c.9440-48G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000662 in 1,577,484 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 0.00069 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00066 (16 hom.)
• Consequence: TNXB ENST00000644971.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.109
• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 6-32049635-C-A is Benign according to our data. Variant chr6-32049635-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 261177.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000644971.2. 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.9440-48G>T		intron	N/A	NP_001352205.1
	TNXB	NM_001428335.1		c.10181-48G>T		intron	N/A	NP_001415264.1
	TNXB	NM_019105.8		c.9434-48G>T		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.9440-48G>T		intron	N/A	ENSP00000496448.1
	TNXB	ENST00000647633.1		c.10181-48G>T		intron	N/A	ENSP00000497649.1
	TNXB	ENST00000375244.7	TSL:5	c.9440-48G>T		intron	N/A	ENSP00000364393.3

Frequencies

GnomAD3 genomes AF: 0.000691 AC: 105 AN: 151992 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.0248

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000177

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00130 AC: 282 AN: 217228 AF XY: 0.00127

Gnomad AFR exome AF: 0.0000758

Gnomad AMR exome AF: 0.0000969

Gnomad ASJ exome AF: 0.0298

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000206

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.000659 AC: 939 AN: 1425374 Hom.: 16 Cov.: 32 AF XY: 0.000673 AC XY: 475 AN XY: 705702

African (AFR) AF: 0.000123 AC: 4 AN: 32520

American (AMR) AF: 0.0000725 AC: 3 AN: 41384

Ashkenazi Jewish (ASJ) AF: 0.0266 AC: 654 AN: 24610

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39166

South Asian (SAS) AF: 0.0000241 AC: 2 AN: 82960

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49854

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4818

European-Non Finnish (NFE) AF: 0.000151 AC: 165 AN: 1091384

Other (OTH) AF: 0.00187 AC: 110 AN: 58678

GnomAD4 genome AF: 0.000690 AC: 105 AN: 152110 Hom.: 2 Cov.: 32 AF XY: 0.000753 AC XY: 56 AN XY: 74352

African (AFR) AF: 0.0000482 AC: 2 AN: 41502

American (AMR) AF: 0.000131 AC: 2 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.0248 AC: 86 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

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

European-Non Finnish (NFE) AF: 0.000177 AC: 12 AN: 67960

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00466 Hom.: 3

Bravo AF: 0.000665

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.3
DANN	Benign	0.48
PhyloP100		-0.11
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: rs373531814; hg19: chr6-32017412;