rs1135809

chr6-32042955-T-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.11921A>C(p.Asn3974Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (32 hom., cov: 0)
  • Exomes 𝑓: 0.40 (26836 hom.)
  • Failed GnomAD Quality Control
• Consequence: TNXB NM_001365276.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.346

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=8.867399E-6).
• BP6: Variant 6-32042955-T-G is Benign according to our data. Variant chr6-32042955-T-G is described in ClinVar as [Benign]. Clinvar id is 261117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32042955-T-G is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.496 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNXB	NM_001365276.2	c.11921A>C	p.Asn3974Thr	missense_variant	38/44	ENST00000644971.2
TNXB	NM_019105.8	c.11915A>C	p.Asn3972Thr	missense_variant	38/44
TNXB	NM_032470.4	c.1208A>C	p.Asn403Thr	missense_variant	7/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNXB	ENST00000644971.2	c.11921A>C	p.Asn3974Thr	missense_variant	38/44		NM_001365276.2

Frequencies

GnomAD3 genomes AF: 0.154 AC: 282 AN: 1832 Hom.: 32 Cov.: 0

Gnomad AFR AF: 0.0866

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.217

Gnomad ASJ AF: 0.313

Gnomad EAS AF: 0.0965

Gnomad SAS AF: 0.198

Gnomad FIN AF: 0.250

Gnomad MID AF: 0.0500

Gnomad NFE AF: 0.192

Gnomad OTH AF: 0.132

GnomAD3 exomes AF: 0.398 AC: 21125 AN: 53052 Hom.: 4698 AF XY: 0.395 AC XY: 10565 AN XY: 26754

Gnomad AFR exome AF: 0.252

Gnomad AMR exome AF: 0.522

Gnomad ASJ exome AF: 0.652

Gnomad EAS exome AF: 0.241

Gnomad SAS exome AF: 0.375

Gnomad FIN exome AF: 0.351

Gnomad NFE exome AF: 0.421

Gnomad OTH exome AF: 0.421

GnomAD4 exome AF: 0.399 AC: 126635 AN: 317224 Hom.: 26836 Cov.: 0 AF XY: 0.398 AC XY: 66392 AN XY: 166918

Gnomad4 AFR exome AF: 0.236

Gnomad4 AMR exome AF: 0.506

Gnomad4 ASJ exome AF: 0.616

Gnomad4 EAS exome AF: 0.267

Gnomad4 SAS exome AF: 0.371

Gnomad4 FIN exome AF: 0.400

Gnomad4 NFE exome AF: 0.407

Gnomad4 OTH exome AF: 0.399

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.154 AC: 281 AN: 1830 Hom.: 32 Cov.: 0 AF XY: 0.160 AC XY: 143 AN XY: 894

Gnomad4 AFR AF: 0.0869

Gnomad4 AMR AF: 0.217

Gnomad4 ASJ AF: 0.313

Gnomad4 EAS AF: 0.0946

Gnomad4 SAS AF: 0.201

Gnomad4 FIN AF: 0.250

Gnomad4 NFE AF: 0.190

Gnomad4 OTH AF: 0.132

Alfa AF: 0.344 Hom.: 909

ExAC AF: 0.0444 AC: 33

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

PreventionGenetics, part of Exact Sciences

-

- -

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	Benign	0.068
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	13
Dann	Benign	0.89
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.0078	N
MetaRNN	Benign	0.0000089	T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.46	T
Vest4		0.032, 0.061
MPC		0.35
ClinPred		0.0030	T
GERP RS		2.9
Varity_R		0.040
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1135809; hg19: chr6-32010732; COSMIC: COSV64475206; COSMIC: COSV64475206;