6-32041372-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001365276.2(TNXB):c.12712C>T(p.Arg4238Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000122 in 147,482 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 23)
  • Exomes 𝑓: 0.000045 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: TNXB NM_001365276.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.03

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.094635606).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNXB	NM_001365276.2	c.12712C>T	p.Arg4238Cys	missense_variant	44/44	ENST00000644971.2
CYP21A2	NM_000500.9	c.*238G>A		3_prime_UTR_variant	10/10	ENST00000644719.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNXB	ENST00000644971.2	c.12712C>T	p.Arg4238Cys	missense_variant	44/44		NM_001365276.2
CYP21A2	ENST00000644719.2	c.*238G>A		3_prime_UTR_variant	10/10		NM_000500.9	P1

Frequencies

GnomAD3 genomes AF: 0.000122 AC: 18 AN: 147364 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000277

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000679

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000602

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000271 AC: 4 AN: 147680 Hom.: 0 AF XY: 0.0000252 AC XY: 2 AN XY: 79444

Gnomad AFR exome AF: 0.000146

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000447

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000365

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000453 AC: 41 AN: 905008 Hom.: 1 Cov.: 12 AF XY: 0.0000495 AC XY: 23 AN XY: 464802

Gnomad4 AFR exome AF: 0.0000469

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000142

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000589

Gnomad4 OTH exome AF: 0.0000477

GnomAD4 genome AF: 0.000122 AC: 18 AN: 147482 Hom.: 0 Cov.: 23 AF XY: 0.0000975 AC XY: 7 AN XY: 71778

Gnomad4 AFR AF: 0.000301

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000453

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000602

Gnomad4 OTH AF: 0.00

ExAC AF: 0.0000306 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	TNXB: PP2 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 18, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Uncertain	0.0
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.077	N
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.095	T;T;T;T;T
MetaSVM	Uncertain	0.37	D
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.34	T
Vest4		0.13, 0.11
MVP		0.36
MPC		3.2
ClinPred		0.71	D
GERP RS		0.83
Varity_R		0.20
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs529618820; hg19: chr6-32009149;