rs143213152

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_005045.4(RELN):c.4408G>A(p.Val1470Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00337 in 1,614,192 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0023 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0035 ( 10 hom. )

Consequence

RELN
NM_005045.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:10

Conservation

PhyloP100: 2.91

Publications

12 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: Orphanet, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Illumina
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=0.009001464).

BP6

Variant 7-103574195-C-T is Benign according to our data. Variant chr7-103574195-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 167585.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00232 (353/152320) while in subpopulation NFE AF = 0.00392 (267/68040). AF 95% confidence interval is 0.00354. There are 0 homozygotes in GnomAd4. There are 150 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 10 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005045.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RELN	NM_005045.4	MANE Select	c.4408G>A	p.Val1470Ile	missense	Exon 30 of 65	NP_005036.2
	RELN	NM_173054.3		c.4408G>A	p.Val1470Ile	missense	Exon 30 of 64	NP_774959.1	P78509-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RELN	ENST00000428762.6	TSL:5 MANE Select	c.4408G>A	p.Val1470Ile	missense	Exon 30 of 65	ENSP00000392423.1	P78509-1
RELN	ENST00000424685.3	TSL:5	c.4408G>A	p.Val1470Ile	missense	Exon 30 of 65	ENSP00000388446.3	J3KQ66
RELN	ENST00000343529.9	TSL:5	c.4408G>A	p.Val1470Ile	missense	Exon 30 of 64	ENSP00000345694.5	P78509-2

Frequencies

GnomAD3 genomes

AF:

0.00232

AC:

353

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000796

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.000660

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00392

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00248

AC:

624

AN:

251442

AF XY:

0.00249

show subpopulations

Gnomad AFR exome

AF:

0.000615

Gnomad AMR exome

AF:

0.00127

Gnomad ASJ exome

AF:

0.00198

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00134

Gnomad NFE exome

AF:

0.00390

Gnomad OTH exome

AF:

0.00244

GnomAD4 exome

AF:

0.00348

AC:

5091

AN:

1461872

Hom.:

Cov.:

AF XY:

0.00336

AC XY:

2446

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.000717

AC:

AN:

33480

American (AMR)

AF:

0.00119

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00142

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00177

AC:

153

AN:

86258

European-Finnish (FIN)

AF:

0.00142

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00407

AC:

4523

AN:

1111992

Other (OTH)

AF:

0.00366

AC:

221

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

288

577

865

1154

1442

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

162

324

486

648

810

<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:

0.00232

AC:

353

AN:

152320

Hom.:

Cov.:

AF XY:

0.00201

AC XY:

150

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.000794

AC:

AN:

41570

American (AMR)

AF:

0.00176

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.000660

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00392

AC:

267

AN:

68040

Other (OTH)

AF:

0.00236

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

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:

0.00343

Hom.:

Bravo

AF:

0.00235

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00314

AC:

ExAC

AF:

0.00265

AC:

322

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00431

EpiControl

AF:

0.00344

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (2)

Inborn genetic diseases (1)

Intellectual disability (1)

Norman-Roberts syndrome (1)

Norman-Roberts syndrome;C4225327:Familial temporal lobe epilepsy 7 (1)

RELN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.063

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.10

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.84

M_CAP

Benign

0.0056

MetaRNN

Benign

0.0090

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.21

PhyloP100

2.9

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.10

REVEL

Benign

0.019

Sift

Benign

0.57

Sift4G

Benign

0.82

Polyphen

0.080

Vest4

0.21

MVP

0.24

MPC

0.14

ClinPred

0.012

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.066

gMVP

0.17

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over