NM_005045.4:c.5108C>G

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

6
8
5

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

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
RELNNM_005045.4 linkc.5108C>G p.Pro1703Arg missense_variant Exon 34 of 65 ENST00000428762.6 NP_005036.2 P78509-1
RELNNM_173054.3 linkc.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
RELNENST00000428762.6 linkc.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.:
0
Cov.:
32
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.:
19
Cov.:
33
AF XY:
0.00454
AC XY:
3301
AN XY:
727206
show subpopulations
African (AFR)
AF:
0.000687
AC:
23
AN:
33478
American (AMR)
AF:
0.00183
AC:
82
AN:
44708
Ashkenazi Jewish (ASJ)
AF:
0.00119
AC:
31
AN:
26132
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39694
South Asian (SAS)
AF:
0.00108
AC:
93
AN:
86256
European-Finnish (FIN)
AF:
0.00680
AC:
363
AN:
53414
Middle Eastern (MID)
AF:
0.000347
AC:
2
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
0
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
0
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.:
0
Cov.:
32
AF XY:
0.00353
AC XY:
263
AN XY:
74428
show subpopulations
African (AFR)
AF:
0.000746
AC:
31
AN:
41550
American (AMR)
AF:
0.00288
AC:
44
AN:
15292
Ashkenazi Jewish (ASJ)
AF:
0.00115
AC:
4
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5182
South Asian (SAS)
AF:
0.000622
AC:
3
AN:
4820
European-Finnish (FIN)
AF:
0.00603
AC:
64
AN:
10608
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
292
European-Non Finnish (NFE)
AF:
0.00568
AC:
386
AN:
68008
Other (OTH)
AF:
0.000945
AC:
2
AN:
2116
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.495
Heterozygous variant carriers
0
27
54
80
107
134
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
10
20
30
40
50
<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.:
0
Bravo
AF:
0.00301
TwinsUK
AF:
0.00405
AC:
15
ALSPAC
AF:
0.00519
AC:
20
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.00535
AC:
46
ExAC
AF:
0.00330
AC:
401
Asia WGS
AF:
0.000289
AC:
1
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
T
BayesDel_noAF
Uncertain
0.090
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.54
D;.;.
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.98
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.94
D;D;D
M_CAP
Benign
0.057
D
MetaRNN
Benign
0.023
T;T;T
MetaSVM
Benign
-0.87
T
MutationAssessor
Pathogenic
2.9
M;M;.
PhyloP100
9.3
PrimateAI
Uncertain
0.64
T
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
T
GERP RS
6.0
Varity_R
0.46
gMVP
0.82
Mutation Taster
=96/4
polymorphism

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

Other links and lift over

dbSNP: rs2229860; hg19: chr7-103205827; API