rs17421133

Variant names:

• chr6-32042495-T-A
• rs17421133
• NM_001365276.2:c.12170A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001365276.2(TNXB):​c.12170A>T​(p.Asn4057Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.3 in 1,610,306 control chromosomes in the GnomAD database, including 78,750 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (6422 hom., cov: 23)
  • Exomes 𝑓: 0.31 (72328 hom.)
• Consequence: TNXB NM_001365276.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.00500
• Publications: 26 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004891485).
• BP6: Variant 6-32042495-T-A is Benign according to our data. Variant chr6-32042495-T-A is described in ClinVar as Benign. ClinVar VariationId is 261120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.37 is higher than 0.05.

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.12170A>T	p.Asn4057Ile	missense	Exon 40 of 44	NP_001352205.1	P22105-3
	TNXB	NM_001428335.1		c.12911A>T	p.Asn4304Ile	missense	Exon 41 of 45	NP_001415264.1	A0A3B3ISX9
	TNXB	NM_019105.8		c.12164A>T	p.Asn4055Ile	missense	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.12170A>T	p.Asn4057Ile	missense	Exon 40 of 44	ENSP00000496448.1	P22105-3
	TNXB	ENST00000451343.4	TSL:1	c.1457A>T	p.Asn486Ile	missense	Exon 9 of 13	ENSP00000407685.1	P22105-2
	TNXB	ENST00000490077.5	TSL:1	n.1997A>T		non_coding_transcript_exon	Exon 10 of 14

Frequencies

GnomAD3 genomes AF: 0.256 AC: 38708 AN: 151314 Hom.: 6412 Cov.: 23

Gnomad AFR AF: 0.0594

Gnomad AMI AF: 0.428

Gnomad AMR AF: 0.377

Gnomad ASJ AF: 0.463

Gnomad EAS AF: 0.214

Gnomad SAS AF: 0.243

Gnomad FIN AF: 0.383

Gnomad MID AF: 0.335

Gnomad NFE AF: 0.319

Gnomad OTH AF: 0.253

GnomAD2 exomes AF: 0.320 AC: 79846 AN: 249888 AF XY: 0.319

Gnomad AFR exome AF: 0.0527

Gnomad AMR exome AF: 0.453

Gnomad ASJ exome AF: 0.462

Gnomad EAS exome AF: 0.201

Gnomad FIN exome AF: 0.380

Gnomad NFE exome AF: 0.332

Gnomad OTH exome AF: 0.317

GnomAD4 exome AF: 0.305 AC: 445066 AN: 1458874 Hom.: 72328 Cov.: 73 AF XY: 0.306 AC XY: 221805 AN XY: 725826

African (AFR) AF: 0.0506 AC: 1694 AN: 33468

American (AMR) AF: 0.443 AC: 19787 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.451 AC: 11789 AN: 26116

East Asian (EAS) AF: 0.269 AC: 10625 AN: 39458

South Asian (SAS) AF: 0.249 AC: 21404 AN: 86056

European-Finnish (FIN) AF: 0.372 AC: 19556 AN: 52598

Middle Eastern (MID) AF: 0.325 AC: 1860 AN: 5726

European-Non Finnish (NFE) AF: 0.307 AC: 340962 AN: 1110528

Other (OTH) AF: 0.289 AC: 17389 AN: 60268

GnomAD4 genome AF: 0.256 AC: 38724 AN: 151432 Hom.: 6422 Cov.: 23 AF XY: 0.261 AC XY: 19311 AN XY: 74006

African (AFR) AF: 0.0592 AC: 2446 AN: 41302

American (AMR) AF: 0.378 AC: 5757 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.463 AC: 1602 AN: 3462

East Asian (EAS) AF: 0.215 AC: 1080 AN: 5024

South Asian (SAS) AF: 0.243 AC: 1155 AN: 4760

European-Finnish (FIN) AF: 0.383 AC: 4036 AN: 10548

Middle Eastern (MID) AF: 0.344 AC: 101 AN: 294

European-Non Finnish (NFE) AF: 0.319 AC: 21625 AN: 67804

Other (OTH) AF: 0.254 AC: 535 AN: 2106

Alfa AF: 0.318 Hom.: 2585

Bravo AF: 0.249

ESP6500AA AF: 0.0754 AC: 228

ESP6500EA AF: 0.315 AC: 1707

ExAC AF: 0.308 AC: 37441

Asia WGS AF: 0.226 AC: 787 AN: 3474

EpiCase AF: 0.342

EpiControl AF: 0.353

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Ehlers-Danlos syndrome due to tenascin-X deficiency (2)
-	-	2	not specified (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	not provided (1)
-	-	1	Vesicoureteral reflux 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.081	T
Eigen	Benign	-0.023
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.038	T
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-0.74	T
PhyloP100		-0.0050
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.9	D
REVEL	Benign	0.23
Sift	Benign	0.071	T
Sift4G	Uncertain	0.025	D
Vest4		0.41
MPC		0.42
ClinPred		0.025	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.26
gMVP		0.42
Mutation Taster		=100/0	polymorphism (auto)

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: rs17421133; hg19: chr6-32010272; COSMIC: COSV64492111; COSMIC: COSV64492111;