6-32041360-C-T

Position:

• chr6-32041360-C-T

Variant summary

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

The NM_001365276.2(TNXB):​c.12724G>A​(p.Gly4242Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000095 (0 hom., cov: 23)
  • Exomes 𝑓: 0.00017 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TNXB NM_001365276.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.99

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]

TNXB (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03850013).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNXB	NM_001365276.2	c.12724G>A	p.Gly4242Arg	missense_variant	44/44	ENST00000644971.2	NP_001352205.1
CYP21A2	NM_000500.9	c.*226C>T		3_prime_UTR_variant	10/10	ENST00000644719.2	NP_000491.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2	c.12724G>A	p.Gly4242Arg	missense_variant	44/44		NM_001365276.2	ENSP00000496448.1
CYP21A2	ENST00000644719.2	c.*226C>T		3_prime_UTR_variant	10/10		NM_000500.9	ENSP00000496625.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 14 AN: 147668 Hom.: 0 Cov.: 23 FAILED QC

Gnomad AFR AF: 0.0000501

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000973

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000150

Gnomad OTH AF: 0.000500

GnomAD3 exomes AF: 0.000143 AC: 21 AN: 147288 Hom.: 0 AF XY: 0.000139 AC XY: 11 AN XY: 79316

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000366

Gnomad ASJ exome AF: 0.000121

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000184

Gnomad OTH exome AF: 0.000234

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000174 AC: 144 AN: 827782 Hom.: 0 Cov.: 11 AF XY: 0.000177 AC XY: 76 AN XY: 428612

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000343

Gnomad4 ASJ exome AF: 0.0000458

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000226

Gnomad4 OTH exome AF: 0.000102

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000948 AC: 14 AN: 147668 Hom.: 0 Cov.: 23 AF XY: 0.0000836 AC XY: 6 AN XY: 71794

Gnomad4 AFR AF: 0.0000501

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000973

Gnomad4 NFE AF: 0.000150

Gnomad4 OTH AF: 0.000500

Alfa AF: 0.0000959 Hom.: 0

ExAC AF: 0.0000319 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Aug 07, 2024

BP4_moderate -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.71
DANN	Benign	0.64
DEOGEN2	Benign	0.054	T;.;T;.;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.53	.;T;T;T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.039	T;T;T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.38	.;.;N;N;.
REVEL	Benign	0.048
Sift	Benign	0.23	.;.;T;T;.
Sift4G	Benign	0.21	.;.;T;T;T
Vest4		0.077, 0.082
MVP		0.10
MPC		1.9
ClinPred		0.033	T
GERP RS		-10
Varity_R		0.059
gMVP		0.25

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: rs763630327; hg19: chr6-32009137;