rs362746

chr7-103539148-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005045.4(RELN):c.7110T>C(p.Val2370=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0288 in 1,614,178 control chromosomes in the GnomAD database, including 1,667 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (152 hom., cov: 33)
  • Exomes 𝑓: 0.029 (1515 hom.)
• Consequence: RELN NM_005045.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.0270

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 7-103539148-A-G is Benign according to our data. Variant chr7-103539148-A-G is described in ClinVar as [Benign]. Clinvar id is 95228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-103539148-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.027 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.188 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RELN	NM_005045.4	c.7110T>C	p.Val2370=	synonymous_variant	45/65	ENST00000428762.6
RELN	NM_173054.3	c.7110T>C	p.Val2370=	synonymous_variant	45/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RELN	ENST00000428762.6	c.7110T>C	p.Val2370=	synonymous_variant	45/65	5	NM_005045.4	P5

Frequencies

GnomAD3 genomes AF: 0.0234 AC: 3568 AN: 152182 Hom.: 153 Cov.: 33

Gnomad AFR AF: 0.00471

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00746

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.199

Gnomad SAS AF: 0.0791

Gnomad FIN AF: 0.0176

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0231

Gnomad OTH AF: 0.0210

GnomAD3 exomes AF: 0.0382 AC: 9603 AN: 251368 Hom.: 573 AF XY: 0.0399 AC XY: 5425 AN XY: 135854

Gnomad AFR exome AF: 0.00357

Gnomad AMR exome AF: 0.00500

Gnomad ASJ exome AF: 0.0109

Gnomad EAS exome AF: 0.216

Gnomad SAS exome AF: 0.0737

Gnomad FIN exome AF: 0.0190

Gnomad NFE exome AF: 0.0219

Gnomad OTH exome AF: 0.0220

GnomAD4 exome AF: 0.0293 AC: 42889 AN: 1461876 Hom.: 1515 Cov.: 32 AF XY: 0.0308 AC XY: 22364 AN XY: 727242

Gnomad4 AFR exome AF: 0.00367

Gnomad4 AMR exome AF: 0.00519

Gnomad4 ASJ exome AF: 0.0106

Gnomad4 EAS exome AF: 0.203

Gnomad4 SAS exome AF: 0.0710

Gnomad4 FIN exome AF: 0.0187

Gnomad4 NFE exome AF: 0.0225

Gnomad4 OTH exome AF: 0.0326

GnomAD4 genome AF: 0.0234 AC: 3564 AN: 152302 Hom.: 152 Cov.: 33 AF XY: 0.0244 AC XY: 1819 AN XY: 74474

Gnomad4 AFR AF: 0.00469

Gnomad4 AMR AF: 0.00745

Gnomad4 ASJ AF: 0.0112

Gnomad4 EAS AF: 0.198

Gnomad4 SAS AF: 0.0790

Gnomad4 FIN AF: 0.0176

Gnomad4 NFE AF: 0.0231

Gnomad4 OTH AF: 0.0217

Alfa AF: 0.0217 Hom.: 26

Bravo AF: 0.0218

Asia WGS AF: 0.130 AC: 450 AN: 3478

EpiCase AF: 0.0209

EpiControl AF: 0.0178

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

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, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 03, 2013	- -
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, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Norman-Roberts syndrome Benign:1

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jul 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	1.0
Dann	Benign	0.57
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

Other links and lift over

dbSNP: rs362746; hg19: chr7-103179595; COSMIC: COSV58991889;