rs204900

chr6-32088803-A-C

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.2761T>G(p.Ser921Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.114 in 1,575,098 control chromosomes in the GnomAD database, including 14,625 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2327 hom., cov: 32)
  • Exomes 𝑓: 0.11 (12298 hom.)
• Consequence: TNXB NM_001365276.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.46

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=0.003803134).
• BP6: Variant 6-32088803-A-C is Benign according to our data. Variant chr6-32088803-A-C is described in ClinVar as [Benign]. Clinvar id is 261131.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32088803-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.284 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNXB	NM_001365276.2	c.2761T>G	p.Ser921Ala	missense_variant	6/44	ENST00000644971.2
TNXB	NM_019105.8	c.2761T>G	p.Ser921Ala	missense_variant	6/44

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNXB	ENST00000644971.2	c.2761T>G	p.Ser921Ala	missense_variant	6/44		NM_001365276.2
TNXB	ENST00000647633.1	c.2761T>G	p.Ser921Ala	missense_variant	6/45			P1
TNXB	ENST00000375244.7	c.2761T>G	p.Ser921Ala	missense_variant	6/44	5

Frequencies

GnomAD3 genomes AF: 0.152 AC: 23139 AN: 152102 Hom.: 2314 Cov.: 32

Gnomad AFR AF: 0.261

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.150

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.107

Gnomad SAS AF: 0.297

Gnomad FIN AF: 0.0619

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.0963

Gnomad OTH AF: 0.189

GnomAD3 exomes AF: 0.136 AC: 26744 AN: 196842 Hom.: 2735 AF XY: 0.148 AC XY: 15583 AN XY: 105436

Gnomad AFR exome AF: 0.253

Gnomad AMR exome AF: 0.0989

Gnomad ASJ exome AF: 0.103

Gnomad EAS exome AF: 0.102

Gnomad SAS exome AF: 0.350

Gnomad FIN exome AF: 0.0647

Gnomad NFE exome AF: 0.0955

Gnomad OTH exome AF: 0.134

GnomAD4 exome AF: 0.110 AC: 157160 AN: 1422878 Hom.: 12298 Cov.: 33 AF XY: 0.118 AC XY: 82787 AN XY: 704100

Gnomad4 AFR exome AF: 0.267

Gnomad4 AMR exome AF: 0.105

Gnomad4 ASJ exome AF: 0.108

Gnomad4 EAS exome AF: 0.109

Gnomad4 SAS exome AF: 0.341

Gnomad4 FIN exome AF: 0.0678

Gnomad4 NFE exome AF: 0.0895

Gnomad4 OTH exome AF: 0.125

GnomAD4 genome AF: 0.152 AC: 23177 AN: 152220 Hom.: 2327 Cov.: 32 AF XY: 0.155 AC XY: 11553 AN XY: 74420

Gnomad4 AFR AF: 0.261

Gnomad4 AMR AF: 0.149

Gnomad4 ASJ AF: 0.111

Gnomad4 EAS AF: 0.106

Gnomad4 SAS AF: 0.297

Gnomad4 FIN AF: 0.0619

Gnomad4 NFE AF: 0.0963

Gnomad4 OTH AF: 0.186

Alfa AF: 0.112 Hom.: 2096

Bravo AF: 0.159

TwinsUK AF: 0.0847 AC: 314

ALSPAC AF: 0.0955 AC: 368

ESP6500AA AF: 0.231 AC: 946

ESP6500EA AF: 0.0906 AC: 758

ExAC AF: 0.121 AC: 14343

Asia WGS AF: 0.249 AC: 866 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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 25, 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 -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Ehlers-Danlos syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 14, 2022

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 17, 2018

This variant is associated with the following publications: (PMID: 16574953, 29379198) -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 31, 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	0.19
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.70
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Benign	0.11	T;.;T;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.83	D
MetaRNN	Benign	0.0038	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Uncertain	0.66	T
Vest4		0.12
ClinPred		0.022	T
GERP RS		5.4
Varity_R		0.14

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: rs204900; hg19: chr6-32056580; COSMIC: COSV64478137; COSMIC: COSV64478137;