rs6457479

Variant names:

• chr6-32042509-G-C
• rs6457479
• NM_001365276.2:c.12156C>G

Your query was ambiguous. Multiple possible variants found:

• chr6-32042509-G-C
• chr6-32042509-G-A
• chr6-32042509-G-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_001365276.2(TNXB):​c.12156C>G​(p.Arg4052Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (0 hom., cov: 20)
  • Exomes 𝑓: 0.0013 (13 hom.)
  • Failed GnomAD Quality Control
• Consequence: TNXB NM_001365276.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.94
• Publications: 3 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]

CYP21A2 (HGNC:2600): (cytochrome P450 family 21 subfamily A member 2) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the endoplasmic reticulum and hydroxylates steroids at the 21 position. Its activity is required for the synthesis of steroid hormones including cortisol and aldosterone. Mutations in this gene cause congenital adrenal hyperplasia. A related pseudogene is located near this gene; gene conversion events involving the functional gene and the pseudogene are thought to account for many cases of steroid 21-hydroxylase deficiency. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

CYP21A2 Gene-Disease associations (from GenCC):

• classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Laboratory for Molecular Medicine
• classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, salt wasting form

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, simple virilizing form

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 6-32042509-G-C is Benign according to our data. Variant chr6-32042509-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 261119.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.94 with no splicing effect.

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.12156C>G	p.Arg4052Arg	synonymous	Exon 40 of 44	NP_001352205.1	P22105-3
	TNXB	NM_001428335.1		c.12897C>G	p.Arg4299Arg	synonymous	Exon 41 of 45	NP_001415264.1	A0A3B3ISX9
	TNXB	NM_019105.8		c.12150C>G	p.Arg4050Arg	synonymous	Exon 40 of 44	NP_061978.6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNXB	ENST00000644971.2	MANE Select	c.12156C>G	p.Arg4052Arg	synonymous	Exon 40 of 44	ENSP00000496448.1	P22105-3
	TNXB	ENST00000451343.4	TSL:1	c.1443C>G	p.Arg481Arg	synonymous	Exon 9 of 13	ENSP00000407685.1	P22105-2
	TNXB	ENST00000490077.5	TSL:1	n.1983C>G		non_coding_transcript_exon	Exon 10 of 14

Frequencies

GnomAD3 genomes AF: 0.00396 AC: 596 AN: 150556 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.00441

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00511

Gnomad ASJ AF: 0.00708

Gnomad EAS AF: 0.00158

Gnomad SAS AF: 0.00531

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.0319

Gnomad NFE AF: 0.00368

Gnomad OTH AF: 0.0102

GnomAD2 exomes AF: 0.00166 AC: 408 AN: 245372 AF XY: 0.00184

Gnomad AFR exome AF: 0.00349

Gnomad AMR exome AF: 0.00153

Gnomad ASJ exome AF: 0.00103

Gnomad EAS exome AF: 0.000889

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00179

Gnomad OTH exome AF: 0.00201

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00128 AC: 1850 AN: 1441036 Hom.: 13 Cov.: 33 AF XY: 0.00145 AC XY: 1037 AN XY: 716456

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00211 AC: 70 AN: 33158

American (AMR) AF: 0.00327 AC: 142 AN: 43452

Ashkenazi Jewish (ASJ) AF: 0.00355 AC: 90 AN: 25348

East Asian (EAS) AF: 0.00147 AC: 57 AN: 38838

South Asian (SAS) AF: 0.00202 AC: 168 AN: 83230

European-Finnish (FIN) AF: 0.000191 AC: 10 AN: 52374

Middle Eastern (MID) AF: 0.0215 AC: 111 AN: 5166

European-Non Finnish (NFE) AF: 0.000962 AC: 1058 AN: 1100144

Other (OTH) AF: 0.00243 AC: 144 AN: 59326

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00394 AC: 593 AN: 150684 Hom.: 0 Cov.: 20 AF XY: 0.00405 AC XY: 298 AN XY: 73636

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00439 AC: 181 AN: 41202

American (AMR) AF: 0.00510 AC: 77 AN: 15096

Ashkenazi Jewish (ASJ) AF: 0.00708 AC: 24 AN: 3390

East Asian (EAS) AF: 0.00158 AC: 8 AN: 5058

South Asian (SAS) AF: 0.00531 AC: 25 AN: 4712

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10606

Middle Eastern (MID) AF: 0.0226 AC: 6 AN: 266

European-Non Finnish (NFE) AF: 0.00368 AC: 248 AN: 67370

Other (OTH) AF: 0.0101 AC: 21 AN: 2072

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00442 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	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)
-	-	1	TNXB-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-3.9
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs6457479; hg19: chr6-32010286; COSMIC: COSV107499816; COSMIC: COSV107499816;