rs61731112

Variant names:

• chr1-175403578-T-G
• rs61731112
• NM_003285.3:c.538A>C

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.538A>C​(p.Asn180His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00526 in 1,614,044 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0034 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0055 (36 hom.)
• Consequence: TNR NM_003285.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 7.88
• Publications: 11 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=0.012104988).
• BP6: Variant 1-175403578-T-G is Benign according to our data. Variant chr1-175403578-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 224863.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00342 (520/152262) while in subpopulation SAS AF = 0.0108 (52/4818). AF 95% confidence interval is 0.00845. There are 2 homozygotes in GnomAd4. There are 243 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNR	NM_003285.3	MANE Select	c.538A>C	p.Asn180His	missense	Exon 4 of 23	NP_003276.3
	TNR	NM_001328635.2		c.-358A>C		5_prime_UTR	Exon 4 of 23	NP_001315564.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNR	ENST00000367674.7	TSL:5 MANE Select	c.538A>C	p.Asn180His	missense	Exon 4 of 23	ENSP00000356646.1
	TNR	ENST00000713954.1		c.538A>C	p.Asn180His	missense	Exon 2 of 20	ENSP00000519247.1
	TNR	ENST00000713977.1		c.499+2638A>C		intron	N/A	ENSP00000519268.1

Frequencies

GnomAD3 genomes AF: 0.00342 AC: 520 AN: 152144 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0108

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00556

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00421 AC: 1057 AN: 251268 AF XY: 0.00490

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00182

Gnomad ASJ exome AF: 0.000696

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000647

Gnomad NFE exome AF: 0.00574

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00545 AC: 7971 AN: 1461782 Hom.: 36 Cov.: 32 AF XY: 0.00557 AC XY: 4047 AN XY: 727198

African (AFR) AF: 0.000657 AC: 22 AN: 33480

American (AMR) AF: 0.00197 AC: 88 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000804 AC: 21 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0103 AC: 891 AN: 86248

European-Finnish (FIN) AF: 0.000562 AC: 30 AN: 53352

Middle Eastern (MID) AF: 0.00399 AC: 23 AN: 5768

European-Non Finnish (NFE) AF: 0.00594 AC: 6602 AN: 1111984

Other (OTH) AF: 0.00487 AC: 294 AN: 60396

GnomAD4 genome AF: 0.00342 AC: 520 AN: 152262 Hom.: 2 Cov.: 32 AF XY: 0.00326 AC XY: 243 AN XY: 74448

African (AFR) AF: 0.000963 AC: 40 AN: 41546

American (AMR) AF: 0.00170 AC: 26 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

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

South Asian (SAS) AF: 0.0108 AC: 52 AN: 4818

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10608

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

European-Non Finnish (NFE) AF: 0.00556 AC: 378 AN: 68020

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.00505 Hom.: 9

Bravo AF: 0.00334

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00547 AC: 47

ExAC AF: 0.00428 AC: 519

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00583

EpiControl AF: 0.00533

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	-	Parkinson disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.35	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.9
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.23
Sift	Benign	0.059	T
Sift4G	Uncertain	0.0040	D
Polyphen		0.94	P
Vest4		0.45
MVP		0.68
MPC		0.59
ClinPred		0.019	T
GERP RS		6.0
Varity_R		0.33
gMVP		0.30
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs61731112; hg19: chr1-175372714;