rs199953230

Variant names:

• chr6-32041874-C-T
• rs199953230
• NM_001365276.2:c.12530G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001365276.2(TNXB):​c.12530G>A​(p.Ser4177Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.067 (23 hom., cov: 12)
  • Exomes 𝑓: 0.063 (733 hom.)
  • Failed GnomAD Quality Control
• Consequence: TNXB NM_001365276.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.728
• Publications: 12 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001997441).
• BP6: Variant 6-32041874-C-T is Benign according to our data. Variant chr6-32041874-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 190377.
• BS2: High Homozygotes in GnomAdExome4 at 733 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.12530G>A	p.Ser4177Asn	missense	Exon 43 of 44	NP_001352205.1	P22105-3
	TNXB	NM_001428335.1		c.13271G>A	p.Ser4424Asn	missense	Exon 44 of 45	NP_001415264.1	A0A3B3ISX9
	TNXB	NM_019105.8		c.12524G>A	p.Ser4175Asn	missense	Exon 43 of 44	NP_061978.6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNXB	ENST00000644971.2	MANE Select	c.12530G>A	p.Ser4177Asn	missense	Exon 43 of 44	ENSP00000496448.1	P22105-3
	TNXB	ENST00000451343.4	TSL:1	c.1817G>A	p.Ser606Asn	missense	Exon 12 of 13	ENSP00000407685.1	P22105-2
	TNXB	ENST00000490077.5	TSL:1	n.2357G>A		non_coding_transcript_exon	Exon 13 of 14

Frequencies

GnomAD3 genomes AF: 0.0672 AC: 5778 AN: 86018 Hom.: 23 Cov.: 12

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.0690

Gnomad AMR AF: 0.0635

Gnomad ASJ AF: 0.0770

Gnomad EAS AF: 0.0198

Gnomad SAS AF: 0.0718

Gnomad FIN AF: 0.0294

Gnomad MID AF: 0.0265

Gnomad NFE AF: 0.0503

Gnomad OTH AF: 0.0685

GnomAD2 exomes AF: 0.0653 AC: 6962 AN: 106564 AF XY: 0.0728

Gnomad AFR exome AF: 0.0565

Gnomad AMR exome AF: 0.0388

Gnomad ASJ exome AF: 0.135

Gnomad EAS exome AF: 0.0144

Gnomad FIN exome AF: 0.0760

Gnomad NFE exome AF: 0.0587

Gnomad OTH exome AF: 0.0680

GnomAD4 exome AF: 0.0630 AC: 32038 AN: 508402 Hom.: 733 Cov.: 6 AF XY: 0.0664 AC XY: 17868 AN XY: 268916

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

African (AFR) AF: 0.130 AC: 1613 AN: 12388

American (AMR) AF: 0.0596 AC: 1652 AN: 27716

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 1553 AN: 15390

East Asian (EAS) AF: 0.00974 AC: 295 AN: 30294

South Asian (SAS) AF: 0.102 AC: 5552 AN: 54404

European-Finnish (FIN) AF: 0.0564 AC: 2149 AN: 38086

Middle Eastern (MID) AF: 0.0714 AC: 147 AN: 2060

European-Non Finnish (NFE) AF: 0.0578 AC: 17447 AN: 301746

Other (OTH) AF: 0.0619 AC: 1630 AN: 26318

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.0672 AC: 5787 AN: 86100 Hom.: 23 Cov.: 12 AF XY: 0.0684 AC XY: 2787 AN XY: 40722

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

African (AFR) AF: 0.124 AC: 2459 AN: 19816

American (AMR) AF: 0.0633 AC: 513 AN: 8106

Ashkenazi Jewish (ASJ) AF: 0.0770 AC: 150 AN: 1948

East Asian (EAS) AF: 0.0199 AC: 73 AN: 3668

South Asian (SAS) AF: 0.0711 AC: 173 AN: 2434

European-Finnish (FIN) AF: 0.0294 AC: 179 AN: 6086

Middle Eastern (MID) AF: 0.0337 AC: 7 AN: 208

European-Non Finnish (NFE) AF: 0.0503 AC: 2127 AN: 42272

Other (OTH) AF: 0.0673 AC: 73 AN: 1084

⚠️ 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: 0.106 Hom.: 64

ExAC AF: 0.0764 AC: 2582

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Ehlers-Danlos syndrome due to tenascin-X deficiency (1)
-	1	-	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	15
DANN	Benign	0.88
DEOGEN2	Benign	0.0021	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.018	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.73
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	1.8	N
REVEL	Benign	0.22
Sift	Benign	0.55	T
Sift4G	Benign	1.0	T
Vest4		0.060
MPC		1.5
ClinPred		0.0059	T
GERP RS		4.7
Varity_R		0.061
gMVP		0.076
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs199953230; hg19: chr6-32009651; COSMIC: COSV64475162; COSMIC: COSV64475162;