Genetic Variant NREP:p.Lys19Glu (chr5-111735456-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_004772.4(NREP):c.55A>G(p.Lys19Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,168 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Consequence

NREP
NM_004772.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.271

Variant links:

Genes affected

NREP (HGNC:16834): (neuronal regeneration related protein) Predicted to be involved in axon regeneration; regulation of neuron differentiation; and regulation of transforming growth factor beta receptor signaling pathway. Predicted to be active in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

NREP links:

STARD4-AS1 (HGNC:44117): (STARD4 antisense RNA 1)

STARD4-AS1 links:

Genome browser will be placed here

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=0.10615522).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NREP	NM_004772.4 link	c.55A>G	p.Lys19Glu	missense_variant	Exon 3 of 4	ENST00000257435.12	NP_004763.1	Q16612-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NREP	ENST00000257435.12 link	c.55A>G	p.Lys19Glu	missense_variant	Exon 3 of 4	1	NM_004772.4	ENSP00000257435.7		Q16612-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.187A>G (p.K63E) alteration is located in exon 3 (coding exon 3) of the NREP gene. This alteration results from a A to G substitution at nucleotide position 187, causing the lysine (K) at amino acid position 63 to be replaced by a glutamic acid (E). 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

0.076

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.19

.;T;T;T;T;.;.;.;T;T;T;T;T;T;.;.

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.65

T;.;.;T;.;T;.;T;.;.;.;.;.;.;T;T

M_CAP

Benign

0.018

MetaRNN

Benign

0.11

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.32

PROVEAN

Uncertain

-3.5

D;N;N;N;N;N;D;D;N;N;N;N;N;N;N;D

REVEL

Benign

0.056

Sift

Benign

0.076

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

Sift4G

Uncertain

0.024

D;T;T;T;T;T;D;D;T;T;T;T;T;T;.;.

Polyphen

0.0010, 0.0050

.;B;B;B;B;.;.;.;B;B;B;B;B;B;B;.

Vest4

0.12

MutPred

0.22

Loss of methylation at K19 (P = 0.0036);Loss of methylation at K19 (P = 0.0036);Loss of methylation at K19 (P = 0.0036);Loss of methylation at K19 (P = 0.0036);Loss of methylation at K19 (P = 0.0036);.;Loss of methylation at K19 (P = 0.0036);Loss of methylation at K19 (P = 0.0036);Loss of methylation at K19 (P = 0.0036);Loss of methylation at K19 (P = 0.0036);Loss of methylation at K19 (P = 0.0036);Loss of methylation at K19 (P = 0.0036);Loss of methylation at K19 (P = 0.0036);Loss of methylation at K19 (P = 0.0036);Loss of methylation at K19 (P = 0.0036);Loss of methylation at K19 (P = 0.0036);

MVP

0.74

MPC

0.39

ClinPred

0.10

GERP RS

-2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.097

gMVP

0.031

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