6-32042349-C-T

Variant names:

• chr6-32042349-C-T
• rs201510617
• NM_001365276.2:c.12224G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001428335.1(TNXB):​c.12965G>A​(p.Arg4322His) variant causes a missense 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4322L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0068 (1 hom., cov: 19)
  • Exomes 𝑓: 0.045 (6 hom.)
  • Failed GnomAD Quality Control
• Consequence: TNXB NM_001428335.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 3.08
• Publications: 15 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: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005153835).
• BP6: Variant 6-32042349-C-T is Benign according to our data. Variant chr6-32042349-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 190375.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001428335.1. 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.12224G>A	p.Arg4075His	missense	Exon 41 of 44	NP_001352205.1
	TNXB	NM_001428335.1		c.12965G>A	p.Arg4322His	missense	Exon 42 of 45	NP_001415264.1
	TNXB	NM_019105.8		c.12218G>A	p.Arg4073His	missense	Exon 41 of 44	NP_061978.6

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNXB	ENST00000644971.2	MANE Select	c.12224G>A	p.Arg4075His	missense	Exon 41 of 44	ENSP00000496448.1
	TNXB	ENST00000451343.4	TSL:1	c.1511G>A	p.Arg504His	missense	Exon 10 of 13	ENSP00000407685.1
	TNXB	ENST00000490077.5	TSL:1	n.2051G>A		non_coding_transcript_exon	Exon 11 of 14

Frequencies

GnomAD3 genomes AF: 0.00683 AC: 848 AN: 124242 Hom.: 1 Cov.: 19

Gnomad AFR AF: 0.0149

Gnomad AMI AF: 0.00120

Gnomad AMR AF: 0.00474

Gnomad ASJ AF: 0.00129

Gnomad EAS AF: 0.00705

Gnomad SAS AF: 0.0136

Gnomad FIN AF: 0.00403

Gnomad MID AF: 0.0149

Gnomad NFE AF: 0.00387

Gnomad OTH AF: 0.00646

GnomAD2 exomes AF: 0.0317 AC: 6690 AN: 210924 AF XY: 0.0355

Gnomad AFR exome AF: 0.0688

Gnomad AMR exome AF: 0.0118

Gnomad ASJ exome AF: 0.0147

Gnomad EAS exome AF: 0.0269

Gnomad FIN exome AF: 0.0134

Gnomad NFE exome AF: 0.0266

Gnomad OTH exome AF: 0.0256

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0445 AC: 55050 AN: 1236720 Hom.: 6 Cov.: 27 AF XY: 0.0430 AC XY: 26655 AN XY: 619428

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

African (AFR) AF: 0.111 AC: 2701 AN: 24320

American (AMR) AF: 0.0179 AC: 699 AN: 39016

Ashkenazi Jewish (ASJ) AF: 0.0215 AC: 491 AN: 22816

East Asian (EAS) AF: 0.0194 AC: 669 AN: 34510

South Asian (SAS) AF: 0.0609 AC: 4535 AN: 74514

European-Finnish (FIN) AF: 0.00695 AC: 348 AN: 50078

Middle Eastern (MID) AF: 0.0210 AC: 107 AN: 5092

European-Non Finnish (NFE) AF: 0.0463 AC: 43303 AN: 935224

Other (OTH) AF: 0.0430 AC: 2197 AN: 51150

⚠️ 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: 0.00684 AC: 850 AN: 124342 Hom.: 1 Cov.: 19 AF XY: 0.00681 AC XY: 413 AN XY: 60682

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

African (AFR) AF: 0.0150 AC: 421 AN: 28094

American (AMR) AF: 0.00474 AC: 61 AN: 12882

Ashkenazi Jewish (ASJ) AF: 0.00129 AC: 4 AN: 3090

East Asian (EAS) AF: 0.00730 AC: 32 AN: 4384

South Asian (SAS) AF: 0.0130 AC: 46 AN: 3538

European-Finnish (FIN) AF: 0.00403 AC: 39 AN: 9670

Middle Eastern (MID) AF: 0.0118 AC: 3 AN: 254

European-Non Finnish (NFE) AF: 0.00387 AC: 232 AN: 59874

Other (OTH) AF: 0.00637 AC: 11 AN: 1726

⚠️ 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: 0.0163 Hom.: 0

ExAC AF: 0.0869 AC: 10532

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Ehlers-Danlos syndrome due to tenascin-X deficiency (2)
-	1	1	not provided (2)
-	-	1	Ehlers-Danlos syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0052	T
MetaSVM	Pathogenic	0.89	D
PhyloP100		3.1
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.21
MPC		3.4
ClinPred		0.072	T
GERP RS		4.8
Varity_R		0.67
gMVP		0.92
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201510617; hg19: chr6-32010126; COSMIC: COSV64472555; COSMIC: COSV64472555;