Variant 14-59745807-T-G 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_021136.3(RTN1):c.916A>C(p.Ile306Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000291 in 1,613,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

RTN1
NM_021136.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0980

Variant links:

Genes affected

RTN1 (HGNC:10467): (reticulon 1) This gene belongs to the family of reticulon encoding genes. Reticulons are associated with the endoplasmic reticulum, and are involved in neuroendocrine secretion or in membrane trafficking in neuroendocrine cells. This gene is considered to be a specific marker for neurological diseases and cancer, and is a potential molecular target for therapy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2011]

RTN1 links:

Genome browser will be placed here

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=0.0322358).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RTN1	NM_021136.3 link	c.916A>C	p.Ile306Leu	missense_variant	2/9	ENST00000267484.10	NP_066959.1	Q16799-1
RTN1	XM_011537063.4 link	c.916A>C	p.Ile306Leu	missense_variant	2/4		XP_011535365.1
RTN1	XM_047431674.1 link	c.916A>C	p.Ile306Leu	missense_variant	2/4		XP_047287630.1
RTN1	XR_007064042.1 link	n.1062A>C		non_coding_transcript_exon_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RTN1	ENST00000267484.10 link	c.916A>C	p.Ile306Leu	missense_variant	2/9	1	NM_021136.3	ENSP00000267484.5		Q16799-1

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152062

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000556

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251434

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.0000578

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.000508

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000151

AC:

AN:

152062

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74280

show subpopulations

Gnomad4 AFR

AF:

0.000556

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000127

Hom.:

Bravo

AF:

0.000144

ExAC

AF:

0.0000412

AC:

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

Aug 09, 2021

The c.916A>C (p.I306L) alteration is located in exon 2 (coding exon 2) of the RTN1 gene. This alteration results from a A to C substitution at nucleotide position 916, causing the isoleucine (I) at amino acid position 306 to be replaced by a leucine (L). 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

0.079

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.85

DANN

Benign

0.89

DEOGEN2

Benign

0.0065

T;T

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.068

LIST_S2

Benign

0.47

T;T

M_CAP

Benign

0.0041

MetaRNN

Benign

0.032

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.6

L;.

PrimateAI

Benign

0.30

PROVEAN

Benign

0.010

N;.

REVEL

Benign

0.014

Sift

Benign

0.37

T;.

Sift4G

Benign

0.78

T;T

Polyphen

0.0

B;.

Vest4

0.17

MutPred

0.24

Gain of catalytic residue at I306 (P = 0.0175);.;

MVP

0.043

MPC

0.10

ClinPred

0.0099

GERP RS

-1.8

Varity_R

0.052

gMVP

0.060

Splicing

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