rs3808039

chr7-103510989-T-C

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.8136A>G(p.Leu2712=) 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:9
• Conservation: PhyloP100: -0.151

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

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	UniProt
RELN	NM_005045.4	c.8136A>G	p.Leu2712=	synonymous_variant	51/65	ENST00000428762.6
SLC26A5-AS1	NR_110141.1	n.1487-1780T>C		intron_variant, non_coding_transcript_variant
RELN	NM_173054.3	c.8136A>G	p.Leu2712=	synonymous_variant	51/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RELN	ENST00000428762.6	c.8136A>G	p.Leu2712=	synonymous_variant	51/65	5	NM_005045.4	P5
SLC26A5-AS1	ENST00000422488.1	n.1487-1780T>C		intron_variant, non_coding_transcript_variant		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

GnomAD3 exomes AF: 0.0475 AC: 11924 AN: 251214 Hom.: 503 AF XY: 0.0488 AC XY: 6623 AN XY: 135772

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

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.: 32 AF XY: 0.0467 AC XY: 3474 AN XY: 74466

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:9

Revision: criteria provided, multiple submitters, no conflicts

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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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	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. -

Norman-Roberts syndrome Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

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

Other links and lift over

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