1-175406219-T-C

Variant names:

• chr1-175406219-T-C
• rs147204644
• NM_003285.3:c.496A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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. 14/22 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 3.79
• Publications: 9 publications found

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: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 224864.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNR	NM_003285.3	MANE Select	c.496A>G	p.Thr166Ala	missense	Exon 3 of 23	NP_003276.3
	TNR	NM_001328635.2		c.-400A>G		5_prime_UTR	Exon 3 of 23	NP_001315564.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNR	ENST00000367674.7	TSL:5 MANE Select	c.496A>G	p.Thr166Ala	missense	Exon 3 of 23	ENSP00000356646.1
	TNR	ENST00000713954.1		c.496A>G	p.Thr166Ala	missense	Exon 1 of 20	ENSP00000519247.1
	TNR	ENST00000713977.1		c.496A>G	p.Thr166Ala	missense	Exon 2 of 20	ENSP00000519268.1

Frequencies

GnomAD3 genomes AF: 0.00405 AC: 616 AN: 152180 Hom.: 2 Cov.: 32

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

GnomAD2 exomes AF: 0.00428 AC: 1062 AN: 248350 AF XY: 0.00432

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 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.: 22 Cov.: 70 AF XY: 0.00470 AC XY: 3419 AN XY: 726960

African (AFR) AF: 0.000807 AC: 27 AN: 33474

American (AMR) AF: 0.00523 AC: 234 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00977 AC: 255 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00147 AC: 127 AN: 86184

European-Finnish (FIN) AF: 0.00227 AC: 121 AN: 53372

Middle Eastern (MID) AF: 0.0104 AC: 60 AN: 5760

European-Non Finnish (NFE) AF: 0.00521 AC: 5795 AN: 1111664

Other (OTH) AF: 0.00528 AC: 319 AN: 60380

GnomAD4 genome AF: 0.00404 AC: 615 AN: 152298 Hom.: 2 Cov.: 32 AF XY: 0.00387 AC XY: 288 AN XY: 74462

African (AFR) AF: 0.00103 AC: 43 AN: 41570

American (AMR) AF: 0.00595 AC: 91 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00720 AC: 25 AN: 3470

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

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4824

European-Finnish (FIN) AF: 0.00207 AC: 22 AN: 10616

Middle Eastern (MID) AF: 0.0274 AC: 8 AN: 292

European-Non Finnish (NFE) AF: 0.00581 AC: 395 AN: 68024

Other (OTH) AF: 0.00711 AC: 15 AN: 2110

Alfa AF: 0.00470 Hom.: 3

Bravo AF: 0.00453

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00752 AC: 29

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00558 AC: 48

ExAC AF: 0.00435 AC: 528

EpiCase AF: 0.00627

EpiControl AF: 0.00563

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TNR: BP4, BS2

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Parkinson disease Uncertain:1

Jan 01, 2016

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

Inborn genetic diseases Benign:1

Dec 28, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	22
DANN	Benign	0.83
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	1.3	L
PhyloP100		3.8
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.19
Sift	Benign	0.18	T
Sift4G	Benign	0.40	T
Polyphen		0.93	P
Vest4		0.27
MVP		0.50
MPC		0.21
ClinPred		0.022	T
GERP RS		5.1
PromoterAI		-0.0069	Neutral
Varity_R		0.19
gMVP		0.24
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs147204644; hg19: chr1-175375355;