rs3808039

Positions:

chr7-103510989-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_005045.4(RELN):c.8136A>G(p.Leu2712Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0398 in 1,613,078 control chromosomes in the GnomAD database, including 1,896 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.047 ( 234 hom., cov: 32)

Exomes 𝑓: 0.039 ( 1662 hom. )

Consequence

RELN
NM_005045.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.151

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 links:

SLC26A5-AS1 (HGNC:55680): (SLC26A5 antisense RNA 1)

SLC26A5-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.7).

BP6

Variant 7-103510989-T-C is Benign according to our data. Variant chr7-103510989-T-C is described in ClinVar as [Benign]. Clinvar id is 95231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-103510989-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.151 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.156 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RELN	NM_005045.4 link	c.8136A>G	p.Leu2712Leu	synonymous_variant	51/65	ENST00000428762.6	NP_005036.2	P78509-1
RELN	NM_173054.3 link	c.8136A>G	p.Leu2712Leu	synonymous_variant	51/64		NP_774959.1	P78509-2
SLC26A5-AS1	NR_110141.1 link	n.1487-1780T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RELN	ENST00000428762.6 link	c.8136A>G	p.Leu2712Leu	synonymous_variant	51/65	5	NM_005045.4	ENSP00000392423.1		P78509-1

Frequencies

GnomAD3 genomes

AF:

0.0474

AC:

7207

AN:

152162

Hom.:

236

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0668

Gnomad AMI

AF:

0.0351

Gnomad AMR

AF:

0.0256

Gnomad ASJ

AF:

0.0161

Gnomad EAS

AF:

0.166

Gnomad SAS

AF:

0.0778

Gnomad FIN

AF:

0.0189

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0352

Gnomad OTH

AF:

0.0508

GnomAD3 exomes

AF:

0.0475

AC:

11924

AN:

251214

Hom.:

503

AF XY:

0.0488

AC XY:

6623

AN XY:

135772

show subpopulations

Gnomad AFR exome

AF:

0.0652

Gnomad AMR exome

AF:

0.0165

Gnomad ASJ exome

AF:

0.0172

Gnomad EAS exome

AF:

0.175

Gnomad SAS exome

AF:

0.0752

Gnomad FIN exome

AF:

0.0198

Gnomad NFE exome

AF:

0.0349

Gnomad OTH exome

AF:

0.0342

GnomAD4 exome

AF:

0.0390

AC:

56993

AN:

1460798

Hom.:

1662

Cov.:

AF XY:

0.0403

AC XY:

29283

AN XY:

726806

show subpopulations

Gnomad4 AFR exome

AF:

0.0629

Gnomad4 AMR exome

AF:

0.0177

Gnomad4 ASJ exome

AF:

0.0164

Gnomad4 EAS exome

AF:

0.158

Gnomad4 SAS exome

AF:

0.0734

Gnomad4 FIN exome

AF:

0.0200

Gnomad4 NFE exome

AF:

0.0334

Gnomad4 OTH exome

AF:

0.0432

GnomAD4 genome

AF:

0.0473

AC:

7202

AN:

152280

Hom.:

234

Cov.:

AF XY:

0.0467

AC XY:

3474

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.0666

Gnomad4 AMR

AF:

0.0256

Gnomad4 ASJ

AF:

0.0161

Gnomad4 EAS

AF:

0.166

Gnomad4 SAS

AF:

0.0775

Gnomad4 FIN

AF:

0.0189

Gnomad4 NFE

AF:

0.0352

Gnomad4 OTH

AF:

0.0517

Alfa

AF:

0.0364

Hom.:

158

Bravo

AF:

0.0476

Asia WGS

AF:

0.124

AC:

430

AN:

3476

EpiCase

AF:

0.0351

EpiControl

AF:

0.0365

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 03, 2012	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 21, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Norman-Roberts syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

1.9

DANN

Benign

0.67

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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