chr6-32042103-G-A

Position:

• chr6-32042103-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001365276.2(TNXB):​c.12378C>T​(p.Asp4126Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (0 hom., cov: 9)
  • Exomes 𝑓: 0.0084 (16 hom.)
  • Failed GnomAD Quality Control
• Consequence: TNXB NM_001365276.2 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -6.51

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]

TNXB (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 6-32042103-G-A is Benign according to our data. Variant chr6-32042103-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 261123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32042103-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-6.51 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0084 (4220/502122) while in subpopulation EAS AF= 0.043 (1355/31478). AF 95% confidence interval is 0.0411. There are 16 homozygotes in gnomad4_exome. There are 2317 alleles in male gnomad4_exome subpopulation. Median coverage is 5. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 16 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNXB	NM_001365276.2	c.12378C>T	p.Asp4126Asp	synonymous_variant	42/44	ENST00000644971.2	NP_001352205.1
TNXB	NM_019105.8	c.12372C>T	p.Asp4124Asp	synonymous_variant	42/44		NP_061978.6
TNXB	NM_032470.4	c.1665C>T	p.Asp555Asp	synonymous_variant	11/13		NP_115859.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNXB	ENST00000644971.2	c.12378C>T	p.Asp4126Asp	synonymous_variant	42/44		NM_001365276.2	ENSP00000496448.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 418 AN: 69564 Hom.: 0 Cov.: 9 FAILED QC

Gnomad AFR AF: 0.00208

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00789

Gnomad ASJ AF: 0.0362

Gnomad EAS AF: 0.0122

Gnomad SAS AF: 0.0113

Gnomad FIN AF: 0.000265

Gnomad MID AF: 0.0202

Gnomad NFE AF: 0.00580

Gnomad OTH AF: 0.00820

GnomAD3 exomes AF: 0.00735 AC: 685 AN: 93208 Hom.: 4 AF XY: 0.00791 AC XY: 386 AN XY: 48780

Gnomad AFR exome AF: 0.000838

Gnomad AMR exome AF: 0.00472

Gnomad ASJ exome AF: 0.0276

Gnomad EAS exome AF: 0.0105

Gnomad SAS exome AF: 0.0121

Gnomad FIN exome AF: 0.00195

Gnomad NFE exome AF: 0.00482

Gnomad OTH exome AF: 0.0110

GnomAD4 exome AF: 0.00840 AC: 4220 AN: 502122 Hom.: 16 Cov.: 5 AF XY: 0.00873 AC XY: 2317 AN XY: 265334

Gnomad4 AFR exome AF: 0.00196

Gnomad4 AMR exome AF: 0.00503

Gnomad4 ASJ exome AF: 0.0295

Gnomad4 EAS exome AF: 0.0430

Gnomad4 SAS exome AF: 0.0117

Gnomad4 FIN exome AF: 0.000913

Gnomad4 NFE exome AF: 0.00443

Gnomad4 OTH exome AF: 0.00731

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00599 AC: 417 AN: 69612 Hom.: 0 Cov.: 9 AF XY: 0.00648 AC XY: 198 AN XY: 30552

Gnomad4 AFR AF: 0.00202

Gnomad4 AMR AF: 0.00787

Gnomad4 ASJ AF: 0.0362

Gnomad4 EAS AF: 0.0123

Gnomad4 SAS AF: 0.0113

Gnomad4 FIN AF: 0.000265

Gnomad4 NFE AF: 0.00580

Gnomad4 OTH AF: 0.00806

Alfa AF: 0.00879 Hom.: 6

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Ehlers-Danlos syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 08, 2021

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	1.9
DANN	Benign	0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs11755562; hg19: chr6-32009880; COSMIC: COSV64480218; COSMIC: COSV64480218;