rs587777683

Positions:

• chr6-32048638-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_001365276.2(TNXB):​c.9770C>T​(p.Thr3257Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000525 in 1,334,512 control chromosomes in the GnomAD database, with no homozygous occurrence. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000052 (0 hom.)
• Consequence: TNXB NM_001365276.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 2.25

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNXB	NM_001365276.2	c.9770C>T	p.Thr3257Ile	missense_variant	29/44	ENST00000644971.2	NP_001352205.1
TNXB	NM_019105.8	c.9764C>T	p.Thr3255Ile	missense_variant	29/44		NP_061978.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2	c.9770C>T	p.Thr3257Ile	missense_variant	29/44		NM_001365276.2	ENSP00000496448
TNXB	ENST00000647633.1	c.10511C>T	p.Thr3504Ile	missense_variant	30/45			ENSP00000497649	P1
TNXB	ENST00000375244.7	c.9770C>T	p.Thr3257Ile	missense_variant	29/44	5		ENSP00000364393

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000168 AC: 3 AN: 178724 Hom.: 0 AF XY: 0.0000307 AC XY: 3 AN XY: 97778

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000361

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000525 AC: 7 AN: 1334512 Hom.: 0 Cov.: 32 AF XY: 0.00000766 AC XY: 5 AN XY: 652650

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000670

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.00000837 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Vesicoureteral reflux 8 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2013

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.076	.;.;.;T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.19	.;T;T;T
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.49	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.7	.;.;D;.
REVEL	Uncertain	0.62
Sift	Benign	0.13	.;.;T;.
Sift4G	Pathogenic	0.0010	.;.;D;D
Vest4		0.69
MVP		0.17
ClinPred		0.44	T
GERP RS		3.1
Varity_R		0.17

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: rs587777683; hg19: chr6-32016415;