Variant 6-5998981-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_016588.3(NRN1):c.424T>C(p.Phe142Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,610,248 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

NRN1
NM_016588.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.58

Variant links:

Genes affected

NRN1 (HGNC:17972): (neuritin 1) This gene encodes a member of the neuritin family, and is expressed in postmitotic-differentiating neurons of the developmental nervous system and neuronal structures associated with plasticity in the adult. The expression of this gene can be induced by neural activity and neurotrophins. The encoded protein contains a consensus cleavage signal found in glycosylphoshatidylinositol (GPI)-anchored proteins. The encoded protein promotes neurite outgrowth and arborization, suggesting its role in promoting neuritogenesis. Overexpression of the encoded protein may be associated with astrocytoma progression. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

NRN1 links:

NRN1 (HGNC:):

NRN1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13995951).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NRN1	NM_016588.3 linkuse as main transcript	c.424T>C	p.Phe142Leu	missense_variant	3/3	ENST00000244766.7	NP_057672.1	Q9NPD7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NRN1	ENST00000244766.7 linkuse as main transcript	c.424T>C	p.Phe142Leu	missense_variant	3/3	1	NM_016588.3	ENSP00000244766.2	Q9NPD7
NRN1	ENST00000622188.4 linkuse as main transcript	c.502T>C	p.Phe168Leu	missense_variant	4/4	2		ENSP00000480483.1	A0A087WWT2
NRN1	ENST00000616243.1 linkuse as main transcript	c.424T>C	p.Phe142Leu	missense_variant	4/4	4		ENSP00000484055.1	Q9NPD7
NRN1	ENST00000495850.1 linkuse as main transcript	n.507T>C		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000123

AC:

AN:

243294

Hom.:

AF XY:

0.0000151

AC XY:

AN XY:

132030

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.00

Gnomad NFE exome

AF:

0.0000273

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000110

AC:

AN:

1458052

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

725234

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

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

Sep 09, 2024

The c.424T>C (p.F142L) alteration is located in exon 3 (coding exon 3) of the NRN1 gene. This alteration results from a T to C substitution at nucleotide position 424, causing the phenylalanine (F) at amino acid position 142 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

Pathogenic

0.71

BayesDel_addAF

Benign

-0.056

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.056

T;.;T

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.019

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.75

.;T;T

M_CAP

Benign

0.0049

MetaRNN

Benign

0.14

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

L;.;L

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.040

N;.;.

REVEL

Uncertain

0.40

Sift

Benign

0.54

T;.;.

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

0.18

B;.;B

Vest4

0.33

MutPred

0.32

Gain of disorder (P = 0.1011);.;Gain of disorder (P = 0.1011);

MVP

0.043

MPC

1.1

ClinPred

0.28

GERP RS

3.1

Varity_R

0.085

gMVP

0.51

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