rs140481433

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PP3_ModerateBP6BS1BS2

The NM_003285.3(TNR):c.1774A>G(p.Thr592Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000748 in 1,587,174 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00027 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00080 ( 3 hom. )

Consequence

TNR
NM_003285.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 7.23

Publications

5 publications found

Variant links:

Genes affected

TNR (HGNC:11953): (tenascin R) This gene encodes a member of the tenascin family of extracellular matrix glycoproteins. The encoded protein is restricted to the central nervous system. The protein may play a role in neurite outgrowth, neural cell adhesion and modulation of sodium channel function. It is a constituent of perineuronal nets. [provided by RefSeq, Aug 2013]

TNR Gene-Disease associations (from GenCC):

neurodevelopmental disorder, nonprogressive, with spasticity and transient opisthotonus
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia

TNR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.875

BP6

Variant 1-175386035-T-C is Benign according to our data. Variant chr1-175386035-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 224861.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00027 (41/152068) while in subpopulation NFE AF = 0.000515 (35/68004). AF 95% confidence interval is 0.00038. There are 0 homozygotes in GnomAd4. There are 20 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003285.3. 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
	TNR	NM_003285.3	MANE Select	c.1774A>G	p.Thr592Ala	missense	Exon 8 of 23	NP_003276.3
	TNR	NM_001328635.2		c.775A>G	p.Thr259Ala	missense	Exon 8 of 23	NP_001315564.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TNR	ENST00000367674.7	TSL:5 MANE Select	c.1774A>G	p.Thr592Ala	missense	Exon 8 of 23	ENSP00000356646.1	Q92752-1
TNR	ENST00000713954.1		c.1774A>G	p.Thr592Ala	missense	Exon 6 of 20	ENSP00000519247.1	A0AAQ5BH57
TNR	ENST00000713977.1		c.1033A>G	p.Thr345Ala	missense	Exon 5 of 20	ENSP00000519268.1	A0AAQ5BHB2

Frequencies

GnomAD3 genomes

AF:

0.000270

AC:

AN:

152068

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000515

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000186

AC:

AN:

236948

AF XY:

0.000156

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000251

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000309

Gnomad OTH exome

AF:

0.000523

GnomAD4 exome

AF:

0.000799

AC:

1146

AN:

1435106

Hom.:

Cov.:

AF XY:

0.000735

AC XY:

522

AN XY:

710150

show subpopulations

African (AFR)

AF:

0.0000924

AC:

AN:

32470

American (AMR)

AF:

0.000266

AC:

AN:

41348

Ashkenazi Jewish (ASJ)

AF:

0.0000400

AC:

AN:

24998

East Asian (EAS)

AF:

0.00

AC:

AN:

39138

South Asian (SAS)

AF:

0.00

AC:

AN:

83992

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52982

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5652

European-Non Finnish (NFE)

AF:

0.000994

AC:

1089

AN:

1095558

Other (OTH)

AF:

0.000712

AC:

AN:

58968

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

123

185

246

308

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

150

200

250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000270

AC:

AN:

152068

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74274

show subpopulations

African (AFR)

AF:

0.0000966

AC:

AN:

41396

American (AMR)

AF:

0.000131

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000515

AC:

AN:

68004

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000486

Hom.:

Bravo

AF:

0.000291

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000189

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

not provided (1)

Parkinson disease (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.87

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.87

MetaSVM

Uncertain

0.075

MutationAssessor

Pathogenic

3.2

PhyloP100

7.2

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-4.8

REVEL

Uncertain

0.53

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.018

Polyphen

0.99

Vest4

0.88

MVP

0.78

MPC

0.78

ClinPred

0.65

GERP RS

5.6

Varity_R

0.79

gMVP

0.79

Mutation Taster

=43/57

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over