6-32081646-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001365276.2(TNXB):c.3764G>A(p.Arg1255His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0851 in 1,590,232 control chromosomes in the GnomAD database, including 6,466 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1255C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.085 (606 hom., cov: 31)
  • Exomes 𝑓: 0.085 (5860 hom.)
• Consequence: TNXB NM_001365276.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.58

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013581812).
• BP6: Variant 6-32081646-C-T is Benign according to our data. Variant chr6-32081646-C-T is described in ClinVar as [Benign]. Clinvar id is 261137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32081646-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.141 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNXB	NM_001365276.2	c.3764G>A	p.Arg1255His	missense_variant	10/44	ENST00000644971.2
TNXB	NM_019105.8	c.3764G>A	p.Arg1255His	missense_variant	10/44

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNXB	ENST00000644971.2	c.3764G>A	p.Arg1255His	missense_variant	10/44		NM_001365276.2
TNXB	ENST00000647633.1	c.4505G>A	p.Arg1502His	missense_variant	11/45			P1
TNXB	ENST00000375244.7	c.3764G>A	p.Arg1255His	missense_variant	10/44	5

Frequencies

GnomAD3 genomes AF: 0.0851 AC: 12907 AN: 151686 Hom.: 611 Cov.: 31

Gnomad AFR AF: 0.100

Gnomad AMI AF: 0.174

Gnomad AMR AF: 0.0436

Gnomad ASJ AF: 0.0954

Gnomad EAS AF: 0.0354

Gnomad SAS AF: 0.152

Gnomad FIN AF: 0.0540

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0877

Gnomad OTH AF: 0.0801

GnomAD3 exomes AF: 0.0770 AC: 16610 AN: 215686 Hom.: 790 AF XY: 0.0813 AC XY: 9520 AN XY: 117058

Gnomad AFR exome AF: 0.105

Gnomad AMR exome AF: 0.0410

Gnomad ASJ exome AF: 0.104

Gnomad EAS exome AF: 0.0337

Gnomad SAS exome AF: 0.127

Gnomad FIN exome AF: 0.0535

Gnomad NFE exome AF: 0.0805

Gnomad OTH exome AF: 0.0790

GnomAD4 exome AF: 0.0852 AC: 122495 AN: 1438428 Hom.: 5860 Cov.: 33 AF XY: 0.0861 AC XY: 61338 AN XY: 712660

Gnomad4 AFR exome AF: 0.108

Gnomad4 AMR exome AF: 0.0440

Gnomad4 ASJ exome AF: 0.104

Gnomad4 EAS exome AF: 0.0205

Gnomad4 SAS exome AF: 0.128

Gnomad4 FIN exome AF: 0.0522

Gnomad4 NFE exome AF: 0.0860

Gnomad4 OTH exome AF: 0.0903

GnomAD4 genome AF: 0.0850 AC: 12904 AN: 151804 Hom.: 606 Cov.: 31 AF XY: 0.0842 AC XY: 6245 AN XY: 74192

Gnomad4 AFR AF: 0.100

Gnomad4 AMR AF: 0.0434

Gnomad4 ASJ AF: 0.0954

Gnomad4 EAS AF: 0.0356

Gnomad4 SAS AF: 0.150

Gnomad4 FIN AF: 0.0540

Gnomad4 NFE AF: 0.0877

Gnomad4 OTH AF: 0.0792

Alfa AF: 0.0880 Hom.: 977

Bravo AF: 0.0855

TwinsUK AF: 0.0787 AC: 292

ALSPAC AF: 0.0786 AC: 303

ESP6500AA AF: 0.0943 AC: 352

ESP6500EA AF: 0.0880 AC: 722

ExAC AF: 0.0696 AC: 8365

Asia WGS AF: 0.0680 AC: 235 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 04, 2018

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.75
Cadd	Benign	0.0010
Dann	Benign	0.67
DEOGEN2	Benign	0.023	T;.;T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0033	N
MetaRNN	Benign	0.0014	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.24	T
Vest4		0.010
ClinPred		0.00030	T
GERP RS		-2.7
Varity_R		0.016

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs12211410; hg19: chr6-32049423;