rs544604053

chr6-32041892-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001365276.2(TNXB):c.12512G>A(p.Arg4171His) 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).

• Frequency:
  • Genomes: 𝑓 0.0041 (8 hom., cov: 12)
  • Exomes 𝑓: 0.00066 (13 hom.)
• Consequence: TNXB NM_001365276.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.230

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009919435).
• BP6: Variant 6-32041892-C-T is Benign according to our data. Variant chr6-32041892-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 224352.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAd at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNXB	NM_001365276.2	c.12512G>A	p.Arg4171His	missense_variant	43/44	ENST00000644971.2
TNXB	NM_019105.8	c.12506G>A	p.Arg4169His	missense_variant	43/44
TNXB	NM_032470.4	c.1799G>A	p.Arg600His	missense_variant	12/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNXB	ENST00000644971.2	c.12512G>A	p.Arg4171His	missense_variant	43/44		NM_001365276.2

Frequencies

GnomAD3 genomes AF: 0.00406 AC: 396 AN: 97580 Hom.: 8 Cov.: 12

Gnomad AFR AF: 0.0140

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00367

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000109

Gnomad OTH AF: 0.000790

GnomAD3 exomes AF: 0.00124 AC: 140 AN: 113134 Hom.: 8 AF XY: 0.00105 AC XY: 64 AN XY: 60982

Gnomad AFR exome AF: 0.0164

Gnomad AMR exome AF: 0.00138

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: 0.0000985

Gnomad OTH exome AF: 0.000836

GnomAD4 exome AF: 0.000660 AC: 394 AN: 596974 Hom.: 13 Cov.: 6 AF XY: 0.000515 AC XY: 162 AN XY: 314618

Gnomad4 AFR exome AF: 0.0145

Gnomad4 AMR exome AF: 0.00223

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000160

Gnomad4 FIN exome AF: 0.0000263

Gnomad4 NFE exome AF: 0.0000416

Gnomad4 OTH exome AF: 0.00157

GnomAD4 genome AF: 0.00406 AC: 397 AN: 97678 Hom.: 8 Cov.: 12 AF XY: 0.00412 AC XY: 187 AN XY: 45362

Gnomad4 AFR AF: 0.0140

Gnomad4 AMR AF: 0.00366

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000109

Gnomad4 OTH AF: 0.000780

Alfa AF: 0.00207 Hom.: 1

ExAC AF: 0.000487 AC: 13

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Vesicoureteral reflux 8 Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

-

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 20, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.26
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Benign	0.098	T;.;T;.;T
Eigen	Benign	-0.035
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.033	N
MetaRNN	Benign	0.0099	T;T;T;T;T
MetaSVM	Benign	-0.67	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.73	T
Vest4		0.17, 0.27
MVP		0.51
MPC		3.4
ClinPred		0.026	T
GERP RS		3.8
Varity_R		0.19
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs544604053; hg19: chr6-32009669;