NM_001365276.2:c.9661G>A

Variant names:

• chr6-32049366-C-T
• rs367685759
• NM_001365276.2:c.9661G>A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001365276.2(TNXB):​c.9661G>A​(p.Val3221Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00262 in 1,612,516 control chromosomes in the GnomAD database, including 151 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V3221V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0028 (151 hom.)
• Consequence: TNXB NM_001365276.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: -0.0220

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027631521).
• BP6: Variant 6-32049366-C-T is Benign according to our data. Variant chr6-32049366-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 209196.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=3, Uncertain_significance=2}. Variant chr6-32049366-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00129 (197/152312) while in subpopulation SAS AF= 0.0371 (179/4826). AF 95% confidence interval is 0.0327. There are 0 homozygotes in gnomad4. There are 137 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 151 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNXB	NM_001365276.2	c.9661G>A	p.Val3221Met	missense_variant	Exon 28 of 44	ENST00000644971.2	NP_001352205.1
TNXB	NM_001428335.1	c.10402G>A	p.Val3468Met	missense_variant	Exon 29 of 45		NP_001415264.1
TNXB	NM_019105.8	c.9655G>A	p.Val3219Met	missense_variant	Exon 28 of 44		NP_061978.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2	c.9661G>A	p.Val3221Met	missense_variant	Exon 28 of 44		NM_001365276.2	ENSP00000496448.1
TNXB	ENST00000647633.1	c.10402G>A	p.Val3468Met	missense_variant	Exon 29 of 45			ENSP00000497649.1
TNXB	ENST00000375244.7	c.9661G>A	p.Val3221Met	missense_variant	Exon 28 of 44	5		ENSP00000364393.3

Frequencies

GnomAD3 genomes AF: 0.00131 AC: 199 AN: 152194 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0375

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00590 AC: 1458 AN: 247064 Hom.: 48 AF XY: 0.00790 AC XY: 1061 AN XY: 134386

Gnomad AFR exome AF: 0.000269

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0450

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000430

Gnomad OTH exome AF: 0.00465

GnomAD4 exome AF: 0.00276 AC: 4035 AN: 1460204 Hom.: 151 Cov.: 32 AF XY: 0.00399 AC XY: 2895 AN XY: 726440

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0409

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000246

Gnomad4 OTH exome AF: 0.00365

GnomAD4 genome AF: 0.00129 AC: 197 AN: 152312 Hom.: 0 Cov.: 33 AF XY: 0.00184 AC XY: 137 AN XY: 74478

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0371

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000244 Hom.: 1

Bravo AF: 0.000317

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000393 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00643 AC: 776

Asia WGS AF: 0.0270 AC: 92 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Dec 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TNXB: BP4, BS1, BS2 -

May 28, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ehlers-Danlos syndrome due to tenascin-X deficiency Uncertain:1

Mar 30, 2015

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been found once in our laboratory in trans with another missense variant [R3211G] in a 40-year-old female with a clinical diagnosis of EDS type III, pain, hypermobility, fevers, night sweats, depression, GI problems, and hyperextensibility in her mother (who was negative for this change). This variant has been seen in our laboratory with other rare variants (phase undetermined) in a 2-year-old male [Q3848K] with tall habitus, joint pain and laxity, hyperelasticity, but also in 3 others without related related symptoms. -

See cases Uncertain:1

Apr 05, 2019

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ehlers-Danlos syndrome Benign:1

Feb 02, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Mar 19, 2020

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	0.13
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.044	.;.;.;T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.69	.;T;T;T
MetaRNN	Benign	0.0028	T;T;T;T
MetaSVM	Benign	-0.81	T
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.7	.;.;N;.
REVEL	Benign	0.12
Sift	Benign	0.033	.;.;D;.
Sift4G	Uncertain	0.0020	.;.;D;D
Vest4		0.35
MVP		0.15
ClinPred		0.022	T
GERP RS		0.37
Varity_R		0.048

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: rs367685759; hg19: chr6-32017143; COSMIC: COSV64492935; COSMIC: COSV64492935;