rs3808039

Variant names:

• chr7-103510989-T-C
• rs3808039
• NM_005045.4:c.8136A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.151
• Publications: 14 publications found

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]

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 95231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
RELN	NM_005045.4	c.8136A>G	p.Leu2712Leu	synonymous_variant	Exon 51 of 65	ENST00000428762.6	NP_005036.2
RELN	NM_173054.3	c.8136A>G	p.Leu2712Leu	synonymous_variant	Exon 51 of 64		NP_774959.1
SLC26A5-AS1	NR_110141.1	n.1487-1780T>C		intron_variant	Intron 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RELN	ENST00000428762.6	c.8136A>G	p.Leu2712Leu	synonymous_variant	Exon 51 of 65	5	NM_005045.4	ENSP00000392423.1

Frequencies

GnomAD3 genomes AF: 0.0474 AC: 7207 AN: 152162 Hom.: 236 Cov.: 32

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

GnomAD2 exomes AF: 0.0475 AC: 11924 AN: 251214 AF XY: 0.0488

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 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.: 30 AF XY: 0.0403 AC XY: 29283 AN XY: 726806

African (AFR) AF: 0.0629 AC: 2102 AN: 33444

American (AMR) AF: 0.0177 AC: 789 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.0164 AC: 429 AN: 26120

East Asian (EAS) AF: 0.158 AC: 6284 AN: 39664

South Asian (SAS) AF: 0.0734 AC: 6330 AN: 86228

European-Finnish (FIN) AF: 0.0200 AC: 1069 AN: 53410

Middle Eastern (MID) AF: 0.0444 AC: 256 AN: 5764

European-Non Finnish (NFE) AF: 0.0334 AC: 37127 AN: 1111138

Other (OTH) AF: 0.0432 AC: 2607 AN: 60344

GnomAD4 genome AF: 0.0473 AC: 7202 AN: 152280 Hom.: 234 Cov.: 32 AF XY: 0.0467 AC XY: 3474 AN XY: 74466

African (AFR) AF: 0.0666 AC: 2770 AN: 41566

American (AMR) AF: 0.0256 AC: 391 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0161 AC: 56 AN: 3472

East Asian (EAS) AF: 0.166 AC: 857 AN: 5174

South Asian (SAS) AF: 0.0775 AC: 374 AN: 4828

European-Finnish (FIN) AF: 0.0189 AC: 201 AN: 10608

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0352 AC: 2395 AN: 68020

Other (OTH) AF: 0.0517 AC: 109 AN: 2110

Alfa AF: 0.0367 Hom.: 194

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

Submissions by phenotype

not specified Benign:6

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 21, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 03, 2012

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Norman-Roberts syndrome Benign:2

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	1.9
DANN	Benign	0.67
PhyloP100		-0.15
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3808039; hg19: chr7-103151436; COSMIC: COSV58999854;