NM_005045.4:c.5108C>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_005045.4(RELN):c.5108C>G(p.Pro1703Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00446 in 1,614,054 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0035 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0046 ( 19 hom. )

Consequence

RELN
NM_005045.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:9

Conservation

PhyloP100: 9.26

Publications

22 publications found

Variant links:

Genes affected

RELN (HGNC:9957): (reelin) This gene encodes a large secreted extracellular matrix protein thought to control cell-cell interactions critical for cell positioning and neuronal migration during brain development. This protein may be involved in schizophrenia, autism, bipolar disorder, major depression and in migration defects associated with temporal lobe epilepsy. Mutations of this gene are associated with autosomal recessive lissencephaly with cerebellar hypoplasia. Two transcript variants encoding distinct isoforms have been identified for this gene. Other transcript variants have been described but their full length nature has not been determined. [provided by RefSeq, Jul 2008]

RELN Gene-Disease associations (from GenCC):

lissencephaly with cerebellar hypoplasia
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Norman-Roberts syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Illumina, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P, PanelApp Australia
familial temporal lobe epilepsy 7
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
autosomal dominant epilepsy with auditory features
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
ankylosing spondylitis
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
complex neurodevelopmental disorder
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

RELN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.023003519).

BP6

Variant 7-103565380-G-C is Benign according to our data. Variant chr7-103565380-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 130125.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00351 (535/152250) while in subpopulation NFE AF = 0.00568 (386/68008). AF 95% confidence interval is 0.00521. There are 0 homozygotes in GnomAd4. There are 263 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 19 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RELN	NM_005045.4 link	c.5108C>G	p.Pro1703Arg	missense_variant	Exon 34 of 65	ENST00000428762.6	NP_005036.2	P78509-1
RELN	NM_173054.3 link	c.5108C>G	p.Pro1703Arg	missense_variant	Exon 34 of 64		NP_774959.1	P78509-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RELN	ENST00000428762.6 link	c.5108C>G	p.Pro1703Arg	missense_variant	Exon 34 of 65	5	NM_005045.4	ENSP00000392423.1		P78509-1

Frequencies

GnomAD3 genomes

AF:

0.00352

AC:

535

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000748

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00288

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00603

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00568

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.00325

AC:

817

AN:

251316

AF XY:

0.00331

show subpopulations

Gnomad AFR exome

AF:

0.000738

Gnomad AMR exome

AF:

0.00182

Gnomad ASJ exome

AF:

0.00119

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00619

Gnomad NFE exome

AF:

0.00474

Gnomad OTH exome

AF:

0.00359

GnomAD4 exome

AF:

0.00455

AC:

6656

AN:

1461804

Hom.:

Cov.:

AF XY:

0.00454

AC XY:

3301

AN XY:

727206

show subpopulations

African (AFR)

AF:

0.000687

AC:

AN:

33478

American (AMR)

AF:

0.00183

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00119

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00108

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00680

AC:

363

AN:

53414

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00524

AC:

5827

AN:

1111962

Other (OTH)

AF:

0.00389

AC:

235

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

392

784

1177

1569

1961

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

204

408

612

816

1020

<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:

0.00351

AC:

535

AN:

152250

Hom.:

Cov.:

AF XY:

0.00353

AC XY:

263

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.000746

AC:

AN:

41550

American (AMR)

AF:

0.00288

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000622

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00603

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00568

AC:

386

AN:

68008

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

107

134

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:

0.00526

Hom.:

Bravo

AF:

0.00301

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00519

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00535

AC:

ExAC

AF:

0.00330

AC:

401

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00447

EpiControl

AF:

0.00403

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:4

Mar 26, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 12, 2016

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 30, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:4

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RELN: BS2 -

Sep 15, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 17, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 19435634, 25648840, 17366345, 16311013) -

Norman-Roberts syndrome

Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Norman-Roberts syndrome;C4225327:Familial temporal lobe epilepsy 7

Benign:1

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

D;.;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.98

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Benign

0.057

MetaRNN

Benign

0.023

T;T;T

MetaSVM

Benign

-0.87

MutationAssessor

Pathogenic

2.9

M;M;.

PhyloP100

9.3

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-4.1

D;D;D

REVEL

Uncertain

0.48

Sift

Uncertain

0.0040

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.94

MVP

0.55

MPC

0.71

ClinPred

0.030

GERP RS

6.0

Varity_R

0.46

gMVP

0.82

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over