rs61910712

Variant names:

• chr6-32084478-T-C
• rs61910712
• NM_001365276.2:c.3380A>G

Your query was ambiguous. Multiple possible variants found:

• chr6-32084478-T-C
• chr6-32084478-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001365276.2(TNXB):​c.3380A>G​(p.Lys1127Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00316 in 1,608,148 control chromosomes in the GnomAD database, including 137 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (65 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (72 hom.)
• Consequence: TNXB NM_001365276.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.03
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• Ehlers-Danlos syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• Ehlers-Danlos syndrome due to tenascin-X deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Illumina, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia
• familial vesicoureteral reflux

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• vesicoureteral reflux 8

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000294466 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0039838552).
• BP6: Variant 6-32084478-T-C is Benign according to our data. Variant chr6-32084478-T-C is described in ClinVar as Benign. ClinVar VariationId is 261134.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0548 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365276.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNXB	NM_001365276.2	MANE Select	c.3380A>G	p.Lys1127Arg	missense	Exon 8 of 44	NP_001352205.1	P22105-3
	TNXB	NM_001428335.1		c.4121A>G	p.Lys1374Arg	missense	Exon 9 of 45	NP_001415264.1	A0A3B3ISX9
	TNXB	NM_019105.8		c.3380A>G	p.Lys1127Arg	missense	Exon 8 of 44	NP_061978.6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNXB	ENST00000644971.2	MANE Select	c.3380A>G	p.Lys1127Arg	missense	Exon 8 of 44	ENSP00000496448.1	P22105-3
	TNXB	ENST00000647633.1		c.4121A>G	p.Lys1374Arg	missense	Exon 9 of 45	ENSP00000497649.1	A0A3B3ISX9
	TNXB	ENST00000375244.7	TSL:5	c.3380A>G	p.Lys1127Arg	missense	Exon 8 of 44	ENSP00000364393.3	P22105-3

Frequencies

GnomAD3 genomes AF: 0.0165 AC: 2510 AN: 152028 Hom.: 66 Cov.: 32

Gnomad AFR AF: 0.0569

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00648

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.0177

GnomAD2 exomes AF: 0.00399 AC: 974 AN: 244128 AF XY: 0.00326

Gnomad AFR exome AF: 0.0566

Gnomad AMR exome AF: 0.00311

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000182

Gnomad OTH exome AF: 0.00234

GnomAD4 exome AF: 0.00176 AC: 2568 AN: 1456002 Hom.: 72 Cov.: 31 AF XY: 0.00152 AC XY: 1102 AN XY: 724026

African (AFR) AF: 0.0597 AC: 1997 AN: 33460

American (AMR) AF: 0.00333 AC: 149 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.000586 AC: 50 AN: 85348

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50550

Middle Eastern (MID) AF: 0.00521 AC: 30 AN: 5760

European-Non Finnish (NFE) AF: 0.0000685 AC: 76 AN: 1110188

Other (OTH) AF: 0.00442 AC: 266 AN: 60228

GnomAD4 genome AF: 0.0165 AC: 2510 AN: 152146 Hom.: 65 Cov.: 32 AF XY: 0.0162 AC XY: 1203 AN XY: 74388

African (AFR) AF: 0.0567 AC: 2352 AN: 41470

American (AMR) AF: 0.00648 AC: 99 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 67994

Other (OTH) AF: 0.0175 AC: 37 AN: 2114

Alfa AF: 0.0125 Hom.: 47

Bravo AF: 0.0194

ESP6500AA AF: 0.0516 AC: 137

ESP6500EA AF: 0.000581 AC: 3

ExAC AF: 0.00431 AC: 512

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Cardiovascular phenotype (1)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.067	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-1.1	T
PhyloP100		2.0
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.13
Sift	Benign	0.48	T
Sift4G	Benign	0.071	T
Vest4		0.30
MVP		0.23
ClinPred		0.017	T
GERP RS		3.1
Varity_R		0.075
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs61910712; hg19: chr6-32052255;