rs183760368

Positions:

• chr6-32056873-G-A

Variant summary

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

The NM_001365276.2(TNXB):​c.7856C>T​(p.Pro2619Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000873 in 1,612,584 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00079 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00088 (0 hom.)
• Consequence: TNXB NM_001365276.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:4
• Conservation: PhyloP100: 2.67

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=0.021029472).
• BP6: Variant 6-32056873-G-A is Benign according to our data. Variant chr6-32056873-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 521772.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Likely_benign=4}. Variant chr6-32056873-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNXB	NM_001365276.2	c.7856C>T	p.Pro2619Leu	missense_variant	23/44	ENST00000644971.2	NP_001352205.1
TNXB	NM_019105.8	c.7856C>T	p.Pro2619Leu	missense_variant	23/44		NP_061978.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2	c.7856C>T	p.Pro2619Leu	missense_variant	23/44		NM_001365276.2	ENSP00000496448
TNXB	ENST00000647633.1	c.8597C>T	p.Pro2866Leu	missense_variant	24/45			ENSP00000497649	P1
TNXB	ENST00000375244.7	c.7856C>T	p.Pro2619Leu	missense_variant	23/44	5		ENSP00000364393

Frequencies

GnomAD3 genomes AF: 0.000749 AC: 114 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00129

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000888 AC: 218 AN: 245398 Hom.: 0 AF XY: 0.000918 AC XY: 123 AN XY: 133930

Gnomad AFR exome AF: 0.000274

Gnomad AMR exome AF: 0.00102

Gnomad ASJ exome AF: 0.00171

Gnomad EAS exome AF: 0.0000558

Gnomad SAS exome AF: 0.000490

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.00121

Gnomad OTH exome AF: 0.00184

GnomAD4 exome AF: 0.000881 AC: 1286 AN: 1460318 Hom.: 0 Cov.: 33 AF XY: 0.000929 AC XY: 675 AN XY: 726420

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.00110

Gnomad4 ASJ exome AF: 0.00134

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000684

Gnomad4 FIN exome AF: 0.0000763

Gnomad4 NFE exome AF: 0.000926

Gnomad4 OTH exome AF: 0.00103

GnomAD4 genome AF: 0.000795 AC: 121 AN: 152266 Hom.: 2 Cov.: 32 AF XY: 0.000860 AC XY: 64 AN XY: 74442

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00129

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00116 Hom.: 0

Bravo AF: 0.000842

ESP6500AA AF: 0.000741 AC: 2

ESP6500EA AF: 0.000580 AC: 3

ExAC AF: 0.000873 AC: 105

EpiCase AF: 0.00218

EpiControl AF: 0.00172

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Ehlers-Danlos syndrome due to tenascin-X deficiency Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 21, 2020	A heterozygous missense variant was identified, NM_001365276.1(TNXB):c.7856C>T in exon 23 of 44 of the TNXB gene (NB: this variant is non-coding in alternative transcripts). This substitution is predicted to create a moderate amino acid change from a proline to a leucine at position 2619 of the protein; NP_001352205.1(TNXB):p.(Pro2619Leu). The proline at this position has very low conservation (100 vertebrates, UCSC), and is not located within a particular domain (NCBI, PDB, UniProt). In silico software predictions of the pathogenicity of this variant are conflicting (PolyPhen2, PROVEAN, MutationAssessor, FATHMM). The variant is present in the gnomAD population database at a global population frequency of 0.087% (241 heterozygotes, 0 homozygotes) with a European sub-population frequency of 0.12%. This variant has been previously reported as a VUS in a clinical case (ClinVar). Based on information available at the time of curation, this variant has been classified as a VUS. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 14, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 26, 2019	The TNXB c.7856C>T (p.Pro2619Leu) variant is a missense variant. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. The variant is reported at a frequency of 0.001658 in the Ashkenazi Jewish population from the Genome Aggregation Database. Based on the limited evidence, the p.Pro2619Leu variant is classified as a variant of uncertain significance for Ehlers-Danlos syndrome due to tenascin-X deficiency. -

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	TNXB: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 20, 2023	See Variant Classification Assertion Criteria. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 29, 2023	BP4 -

Ehlers-Danlos syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 31, 2021

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 13, 2023

Variant summary: TNXB c.7856C>T (p.Pro2619Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00087 in 1612584 control chromosomes, including 2 homozygotes, predominantly at a frequency of 0.0059 within the Middle Eastern subpopulation (gnomAD v4). The observed variant frequency within Middle Eastern control individuals in the gnomAD database is approximately 5.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in TNXB causing Ehlers-Danlos-like syndrome phenotype (0.0011), strongly suggesting that the variant is a benign polymorphism. c.7856C>T has been reported in the literature in the heterozygous state in at least one individual affected with distal myopathy (e.g., Evila_2017), however without strong evidence for causality due to a co-occurring pathogenic TTN truncating variant. This report therefore does not provide unequivocal conclusions about association of the variant with Ehlers-Danlos-like syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication was ascertained in the context of this evaluation (PMID: 27796757). Six submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (likely benign, n = 3; VUS, n = 3). Based on the evidence outlined above, the variant was classified as likely benign. -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 14, 2024

This alteration is classified as likely 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	0.10
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T;.;T;T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.61	.;T;T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.021	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.92	D;D
PrimateAI	Benign	0.32	T
PROVEAN	Pathogenic	-5.2	.;.;D;.
REVEL	Benign	0.19
Sift	Uncertain	0.0080	.;.;D;.
Sift4G	Uncertain	0.010	.;.;D;D
Vest4		0.099
MVP		0.26
ClinPred		0.096	T
GERP RS		4.1
Varity_R		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs183760368; hg19: chr6-32024650;