Variant 11-63719650-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001265589.2(RTN3):c.1148C>T(p.Thr383Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000105 in 1,613,832 control chromosomes in the GnomAD database, including 1 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 1 hom. )

Consequence

RTN3
NM_001265589.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.80

Variant links:

Genes affected

RTN3 (HGNC:10469): (reticulon 3) This gene belongs to the reticulon family of highly conserved genes that are preferentially expressed in neuroendocrine tissues. This family of proteins interact with, and modulate the activity of beta-amyloid converting enzyme 1 (BACE1), and the production of amyloid-beta. An increase in the expression of any reticulon protein substantially reduces the production of amyloid-beta, suggesting that reticulon proteins are negative modulators of BACE1 in cells. Alternatively spliced transcript variants encoding different isoforms have been found for this gene, and pseudogenes of this gene are located on chromosomes 4 and 12. [provided by RefSeq, May 2012]

RTN3 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.044346243).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RTN3	NM_001265589.2 linkuse as main transcript	c.1148C>T	p.Thr383Ile	missense_variant	3/9	ENST00000377819.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RTN3	ENST00000377819.10 linkuse as main transcript	c.1148C>T	p.Thr383Ile	missense_variant	3/9	1	NM_001265589.2		O95197-1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000116

AC:

AN:

250202

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

135498

show subpopulations

Gnomad AFR exome

AF:

0.0000633

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000556

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.000657

GnomAD4 exome

AF:

0.000108

AC:

158

AN:

1461660

Hom.:

Cov.:

AF XY:

0.000116

AC XY:

AN XY:

727144

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000675

Gnomad4 NFE exome

AF:

0.000103

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000236

Hom.:

Bravo

AF:

0.0000907

ExAC

AF:

0.000140

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 27, 2023

The c.1091C>T (p.T364I) alteration is located in exon 2 (coding exon 2) of the RTN3 gene. This alteration results from a C to T substitution at nucleotide position 1091, causing the threonine (T) at amino acid position 364 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.021

T;.;.

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.71

T;T;T

M_CAP

Benign

0.0091

MetaRNN

Benign

0.044

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

L;.;.

MutationTaster

Benign

1.0

N;N;N;N;N;N;N

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.91

N;N;N

REVEL

Benign

0.077

Sift

Benign

0.090

T;T;T

Sift4G

Benign

0.25

T;T;T

Polyphen

0.48

P;P;.

Vest4

0.075

MVP

0.39

MPC

0.066

ClinPred

0.062

GERP RS

4.1

Varity_R

0.090

gMVP

0.054

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

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