rs62402693

Positions:

• chr6-32045210-A-G

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.10723T>C​(p.Ser3575Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.121 in 1,553,184 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S3575S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.15 (0 hom., cov: 24)
  • Exomes 𝑓: 0.12 (1 hom.)
• Consequence: TNXB NM_001365276.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.15

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=0.0024795234).
• BP6: Variant 6-32045210-A-G is Benign according to our data. Variant chr6-32045210-A-G is described in ClinVar as [Benign]. Clinvar id is 403558.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.253 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNXB	NM_001365276.2	c.10723T>C	p.Ser3575Pro	missense_variant	32/44	ENST00000644971.2	NP_001352205.1
TNXB	NM_019105.8	c.10717T>C	p.Ser3573Pro	missense_variant	32/44		NP_061978.6
TNXB	NM_032470.4	c.10T>C	p.Ser4Pro	missense_variant	1/13		NP_115859.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2	c.10723T>C	p.Ser3575Pro	missense_variant	32/44		NM_001365276.2	ENSP00000496448

Frequencies

GnomAD3 genomes AF: 0.149 AC: 21454 AN: 144376 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.257

Gnomad AMI AF: 0.0256

Gnomad AMR AF: 0.145

Gnomad ASJ AF: 0.0891

Gnomad EAS AF: 0.0833

Gnomad SAS AF: 0.166

Gnomad FIN AF: 0.0554

Gnomad MID AF: 0.204

Gnomad NFE AF: 0.109

Gnomad OTH AF: 0.173

GnomAD3 exomes AF: 0.114 AC: 26206 AN: 230376 Hom.: 0 AF XY: 0.117 AC XY: 14705 AN XY: 126064

Gnomad AFR exome AF: 0.245

Gnomad AMR exome AF: 0.0943

Gnomad ASJ exome AF: 0.0811

Gnomad EAS exome AF: 0.0810

Gnomad SAS exome AF: 0.190

Gnomad FIN exome AF: 0.0569

Gnomad NFE exome AF: 0.102

Gnomad OTH exome AF: 0.125

GnomAD4 exome AF: 0.118 AC: 166189 AN: 1408718 Hom.: 1 Cov.: 33 AF XY: 0.119 AC XY: 83568 AN XY: 700502

Gnomad4 AFR exome AF: 0.266

Gnomad4 AMR exome AF: 0.103

Gnomad4 ASJ exome AF: 0.0877

Gnomad4 EAS exome AF: 0.0814

Gnomad4 SAS exome AF: 0.188

Gnomad4 FIN exome AF: 0.0620

Gnomad4 NFE exome AF: 0.113

Gnomad4 OTH exome AF: 0.132

GnomAD4 genome AF: 0.149 AC: 21472 AN: 144466 Hom.: 0 Cov.: 24 AF XY: 0.147 AC XY: 10338 AN XY: 70560

Gnomad4 AFR AF: 0.257

Gnomad4 AMR AF: 0.145

Gnomad4 ASJ AF: 0.0891

Gnomad4 EAS AF: 0.0833

Gnomad4 SAS AF: 0.166

Gnomad4 FIN AF: 0.0554

Gnomad4 NFE AF: 0.109

Gnomad4 OTH AF: 0.171

Alfa AF: 0.133 Hom.: 0

ExAC AF: 0.124 AC: 14552

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Uncertain	0.078	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;.;T;.;T
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.062
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.81	.;T;T;T;D
MetaRNN	Benign	0.0025	T;T;T;T;T
MetaSVM	Benign	-0.60	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.5	.;.;D;D;.
REVEL	Uncertain	0.42
Sift	Uncertain	0.010	.;.;D;D;.
Sift4G	Uncertain	0.0040	.;.;D;D;D
Vest4		0.28, 0.44
MPC		4.1
ClinPred		0.031	T
GERP RS		2.3
Varity_R		0.70
gMVP		0.69

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: rs62402693; hg19: chr6-32012987; COSMIC: COSV64472579; COSMIC: COSV64472579;