6-32041356-C-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001365276.2(TNXB):c.12728G>T(p.Gly4243Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 23)
  • Exomes 𝑓: 0.00035 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TNXB NM_001365276.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.561

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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02658552).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNXB	NM_001365276.2	c.12728G>T	p.Gly4243Val	missense_variant	44/44	ENST00000644971.2
CYP21A2	NM_000500.9	c.*222C>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.12728G>T	p.Gly4243Val	missense_variant	44/44		NM_001365276.2
CYP21A2	ENST00000644719.2	c.*222C>A		3_prime_UTR_variant	10/10		NM_000500.9	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 194 AN: 145794 Hom.: 0 Cov.: 23 FAILED QC

Gnomad AFR AF: 0.00190

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00273

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00357

Gnomad NFE AF: 0.00105

Gnomad OTH AF: 0.00412

GnomAD3 exomes AF: 0.0000682 AC: 10 AN: 146582 Hom.: 0 AF XY: 0.0000760 AC XY: 6 AN XY: 78940

Gnomad AFR exome AF: 0.000297

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000121

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000898

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000923

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000349 AC: 273 AN: 783170 Hom.: 0 Cov.: 11 AF XY: 0.000349 AC XY: 142 AN XY: 407078

Gnomad4 AFR exome AF: 0.000410

Gnomad4 AMR exome AF: 0.000231

Gnomad4 ASJ exome AF: 0.000802

Gnomad4 EAS exome AF: 0.0000300

Gnomad4 SAS exome AF: 0.000178

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000403

Gnomad4 OTH exome AF: 0.000373

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00134 AC: 195 AN: 145926 Hom.: 0 Cov.: 23 AF XY: 0.00137 AC XY: 97 AN XY: 70972

Gnomad4 AFR AF: 0.00191

Gnomad4 AMR AF: 0.00156

Gnomad4 ASJ AF: 0.00273

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00209

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00105

Gnomad4 OTH AF: 0.00407

Alfa AF: 0.000911 Hom.: 0

ExAC AF: 0.000175 AC: 11

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 09, 2021

The c.12722G>T (p.G4241V) alteration is located in exon 44 (coding exon 43) of the TNXB gene. This alteration results from a G to T substitution at nucleotide position 12722, causing the glycine (G) at amino acid position 4241 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	21
Dann	Benign	0.95
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.18	N
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.027	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.45	T
Vest4		0.24, 0.26
MVP		0.31
MPC		2.9
ClinPred		0.12	T
GERP RS		1.6
Varity_R		0.18
gMVP		0.47

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

Publications

LitVar

Other links and lift over

dbSNP: rs56148109; hg19: chr6-32009133; COSMIC: COSV104682825; COSMIC: COSV104682825;