Genetic Variant RTN4:p.Leu981Phe (chr2-55025158-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_020532.5(RTN4):c.2941C>T(p.Leu981Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000336 in 1,613,716 control chromosomes in the GnomAD database, including 2 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00033 ( 2 hom. )

Consequence

RTN4
NM_020532.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.51

Publications

6 publications found

Variant links:

Genes affected

RTN4 (HGNC:14085): (reticulon 4) 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. The product of this gene is a potent neurite outgrowth inhibitor which may also help block the regeneration of the central nervous system in higher vertebrates. Alternatively spliced transcript variants derived both from differential splicing and differential promoter usage and encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

RTN4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009067297).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020532.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RTN4	NM_020532.5	MANE Select	c.2941C>T	p.Leu981Phe	missense	Exon 3 of 9	NP_065393.1	Q9NQC3-1
RTN4	NM_001321859.2		c.2323C>T	p.Leu775Phe	missense	Exon 3 of 9	NP_001308788.1	Q9NQC3-6
RTN4	NM_001321860.1		c.2323C>T	p.Leu775Phe	missense	Exon 3 of 9	NP_001308789.1	Q9NQC3-6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RTN4	ENST00000337526.11	TSL:1 MANE Select	c.2941C>T	p.Leu981Phe	missense	Exon 3 of 9	ENSP00000337838.6	Q9NQC3-1
RTN4	ENST00000357376.7	TSL:1	c.2323C>T	p.Leu775Phe	missense	Exon 3 of 9	ENSP00000349944.3	Q9NQC3-6
RTN4	ENST00000394611.6	TSL:1	c.2323C>T	p.Leu775Phe	missense	Exon 3 of 9	ENSP00000378109.2	Q9NQC3-6

Frequencies

GnomAD3 genomes

AF:

0.000368

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00605

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000382

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.000371

AC:

AN:

250520

AF XY:

0.000377

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000232

Gnomad ASJ exome

AF:

0.00438

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000336

Gnomad OTH exome

AF:

0.000491

GnomAD4 exome

AF:

0.000333

AC:

487

AN:

1461440

Hom.:

Cov.:

AF XY:

0.000341

AC XY:

248

AN XY:

727004

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33450

American (AMR)

AF:

0.000269

AC:

AN:

44672

Ashkenazi Jewish (ASJ)

AF:

0.00532

AC:

139

AN:

26106

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00

AC:

AN:

86230

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.000273

AC:

303

AN:

1111768

Other (OTH)

AF:

0.000513

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

102

128

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000368

AC:

AN:

152276

Hom.:

Cov.:

AF XY:

0.000389

AC XY:

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41566

American (AMR)

AF:

0.000393

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00605

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000382

AC:

AN:

68018

Other (OTH)

AF:

0.00142

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000614

Hom.:

Bravo

AF:

0.000370

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000428

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000533

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.71

M_CAP

Benign

0.0082

MetaRNN

Benign

0.0091

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

PhyloP100

1.5

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.5

REVEL

Benign

0.063

Sift

Benign

0.040

Sift4G

Benign

0.062

Polyphen

0.93

Vest4

0.095

MVP

0.40

MPC

0.033

ClinPred

0.047

GERP RS

1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.069

gMVP

0.085

Mutation Taster

=96/4

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over