rs140481433

chr1-175386035-T-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP3_Moderate BS1_Supporting BS2

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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00080 (3 hom.)
• Consequence: TNR NM_003285.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.23

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.875
• 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 male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 41 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNR	NM_003285.3	c.1774A>G	p.Thr592Ala	missense_variant	8/23	ENST00000367674.7
TNR	NM_001328635.2	c.775A>G	p.Thr259Ala	missense_variant	8/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNR	ENST00000367674.7	c.1774A>G	p.Thr592Ala	missense_variant	8/23	5	NM_003285.3	P1

Frequencies

GnomAD3 genomes AF: 0.000270 AC: 41 AN: 152068 Hom.: 0 Cov.: 31

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

GnomAD3 exomes AF: 0.000186 AC: 44 AN: 236948 Hom.: 0 AF XY: 0.000156 AC XY: 20 AN XY: 128232

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 SAS 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.: 3 Cov.: 55 AF XY: 0.000735 AC XY: 522 AN XY: 710150

Gnomad4 AFR exome AF: 0.0000924

Gnomad4 AMR exome AF: 0.000266

Gnomad4 ASJ exome AF: 0.0000400

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000994

Gnomad4 OTH exome AF: 0.000712

GnomAD4 genome AF: 0.000270 AC: 41 AN: 152068 Hom.: 0 Cov.: 31 AF XY: 0.000269 AC XY: 20 AN XY: 74274

Gnomad4 AFR AF: 0.0000966

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000515

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000516 Hom.: 0

Bravo AF: 0.000291

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000189 AC: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 08, 2022

The c.1774A>G (p.T592A) alteration is located in exon 8 (coding exon 6) of the TNR gene. This alteration results from a A to G substitution at nucleotide position 1774, causing the threonine (T) at amino acid position 592 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Parkinson disease Uncertain:1

Uncertain significance, criteria provided, single submitter

research

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

Jan 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.060
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D;D
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Uncertain	0.075	D
MutationAssessor	Pathogenic	3.2	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-4.8	D;D
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.018	D;D
Polyphen		0.99	D;D
Vest4		0.88
MVP		0.78
MPC		0.78
ClinPred		0.65	D
GERP RS		5.6
Varity_R		0.79
gMVP		0.79

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

LitVar

Other links and lift over

dbSNP: rs140481433; hg19: chr1-175355171;