chr1-175406219-T-C

Position:

chr1-175406219-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_003285.3(TNR):c.496A>G(p.Thr166Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00468 in 1,613,638 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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 0.0040 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0047 ( 22 hom. )

Consequence

TNR
NM_003285.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 3.79

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010126919).

BP6

Variant 1-175406219-T-C is Benign according to our data. Variant chr1-175406219-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 224864.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=1}. Variant chr1-175406219-T-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00404 (615/152298) while in subpopulation AMR AF= 0.00595 (91/15302). AF 95% confidence interval is 0.00533. There are 2 homozygotes in gnomad4. There are 288 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 615 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNR	NM_003285.3 linkuse as main transcript	c.496A>G	p.Thr166Ala	missense_variant	3/23	ENST00000367674.7	NP_003276.3	Q92752-1A1L306
TNR	NM_001328635.2 linkuse as main transcript	c.-400A>G		5_prime_UTR_variant	3/23		NP_001315564.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNR	ENST00000367674.7 linkuse as main transcript	c.496A>G	p.Thr166Ala	missense_variant	3/23	5	NM_003285.3	ENSP00000356646.1		Q92752-1
TNR	ENST00000422274.2 linkuse as main transcript	c.145A>G	p.Thr49Ala	missense_variant	1/4	5		ENSP00000403413.2		H0Y668

Frequencies

GnomAD3 genomes

AF:

0.00405

AC:

616

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00104

Gnomad AMI

AF:

0.00768

Gnomad AMR

AF:

0.00595

Gnomad ASJ

AF:

0.00720

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.00207

Gnomad MID

AF:

0.0287

Gnomad NFE

AF:

0.00581

Gnomad OTH

AF:

0.00718

GnomAD3 exomes

AF:

0.00428

AC:

1062

AN:

248350

Hom.:

AF XY:

0.00432

AC XY:

580

AN XY:

134398

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.00550

Gnomad ASJ exome

AF:

0.00997

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00151

Gnomad FIN exome

AF:

0.00241

Gnomad NFE exome

AF:

0.00568

Gnomad OTH exome

AF:

0.00573

GnomAD4 exome

AF:

0.00475

AC:

6938

AN:

1461340

Hom.:

Cov.:

AF XY:

0.00470

AC XY:

3419

AN XY:

726960

show subpopulations

Gnomad4 AFR exome

AF:

0.000807

Gnomad4 AMR exome

AF:

0.00523

Gnomad4 ASJ exome

AF:

0.00977

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00147

Gnomad4 FIN exome

AF:

0.00227

Gnomad4 NFE exome

AF:

0.00521

Gnomad4 OTH exome

AF:

0.00528

GnomAD4 genome

AF:

0.00404

AC:

615

AN:

152298

Hom.:

Cov.:

AF XY:

0.00387

AC XY:

288

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.00103

Gnomad4 AMR

AF:

0.00595

Gnomad4 ASJ

AF:

0.00720

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00187

Gnomad4 FIN

AF:

0.00207

Gnomad4 NFE

AF:

0.00581

Gnomad4 OTH

AF:

0.00711

Alfa

AF:

0.00497

Hom.:

Bravo

AF:

0.00453

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00752

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00558

AC:

ExAC

AF:

0.00435

AC:

528

EpiCase

AF:

0.00627

EpiControl

AF:

0.00563

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	TNR: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Parkinson disease

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Jan 01, 2016

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2021

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

0.067

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Benign

0.83

DEOGEN2

Benign

0.32

T;T

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.84

.;T

M_CAP

Benign

0.020

MetaRNN

Benign

0.010

T;T

MetaSVM

Benign

-0.62

MutationAssessor

Benign

1.3

L;L

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.4

N;N

REVEL

Benign

0.19

Sift

Benign

0.18

T;T

Sift4G

Benign

0.40

T;T

Polyphen

0.93

P;P

Vest4

0.27

MVP

0.50

MPC

0.21

ClinPred

0.022

GERP RS

5.1

Varity_R

0.19

gMVP

0.24

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over