rs199953230

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

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. 14/21 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

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]

ACMG classification

Our verdict: Benign. The variant received -13 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 id is 190377.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}. Variant chr6-32041874-C-T is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.125 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNXB	NM_001365276.2	c.12530G>A	p.Ser4177Asn	missense_variant	Exon 43 of 44	ENST00000644971.2	NP_001352205.1
CYP21A2	NM_000500.9	c.*740C>T		downstream_gene_variant		ENST00000644719.2	NP_000491.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2	c.12530G>A	p.Ser4177Asn	missense_variant	Exon 43 of 44		NM_001365276.2	ENSP00000496448.1
CYP21A2	ENST00000644719.2	c.*740C>T		downstream_gene_variant			NM_000500.9	ENSP00000496625.1

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

Gnomad4 AFR exome AF: 0.130 AC: 1613 AN: 12388

Gnomad4 AMR exome AF: 0.0596 AC: 1652 AN: 27716

Gnomad4 ASJ exome AF: 0.101 AC: 1553 AN: 15390

Gnomad4 EAS exome AF: 0.00974 AC: 295 AN: 30294

Gnomad4 SAS exome AF: 0.102 AC: 5552 AN: 54404

Gnomad4 FIN exome AF: 0.0564 AC: 2149 AN: 38086

Gnomad4 NFE exome AF: 0.0578 AC: 17447 AN: 301746

Gnomad4 Remaining exome AF: 0.0619 AC: 1630 AN: 26318

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

Gnomad4 AFR AF: 0.124 AC: 0.124092 AN: 0.124092

Gnomad4 AMR AF: 0.0633 AC: 0.0632865 AN: 0.0632865

Gnomad4 ASJ AF: 0.0770 AC: 0.0770021 AN: 0.0770021

Gnomad4 EAS AF: 0.0199 AC: 0.0199019 AN: 0.0199019

Gnomad4 SAS AF: 0.0711 AC: 0.0710764 AN: 0.0710764

Gnomad4 FIN AF: 0.0294 AC: 0.0294118 AN: 0.0294118

Gnomad4 NFE AF: 0.0503 AC: 0.050317 AN: 0.050317

Gnomad4 OTH AF: 0.0673 AC: 0.0673432 AN: 0.0673432

Alfa AF: 0.106 Hom.: 64

ExAC AF: 0.0764 AC: 2582

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Ehlers-Danlos syndrome due to tenascin-X deficiency Uncertain:1

Jan 01, 2015

Pediatric Services, National Institutes of Health, Clinical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided Uncertain:1

Mar 12, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BP4_strong -

not specified Benign:1

Jun 25, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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;T;T;T
MetaRNN	Benign	0.0020	T;T;T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	1.8	.;.;N;N;.
REVEL	Benign	0.22
Sift	Benign	0.55	.;.;T;T;.
Sift4G	Benign	1.0	.;.;T;T;T
Vest4		0.060, 0.092
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

Publications

LitVar

Other links and lift over

dbSNP: rs199953230; hg19: chr6-32009651; COSMIC: COSV64475162; COSMIC: COSV64475162;