rs607755

Positions:

• chr7-103749507-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005045.4(RELN):​c.578-3T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.533 in 1,601,616 control chromosomes in the GnomAD database, including 230,696 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (18953 hom., cov: 32)
  • Exomes 𝑓: 0.54 (211743 hom.)
• Consequence: RELN NM_005045.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00003143
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.0830

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 7-103749507-A-G is Benign according to our data. Variant chr7-103749507-A-G is described in ClinVar as [Benign]. Clinvar id is 95224.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-103749507-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.544 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RELN	NM_005045.4	c.578-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000428762.6	NP_005036.2
RELN	NM_173054.3	c.578-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_774959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RELN	ENST00000428762.6	c.578-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_005045.4	ENSP00000392423	P5

Frequencies

GnomAD3 genomes AF: 0.497 AC: 75403 AN: 151846 Hom.: 18925 Cov.: 32

Gnomad AFR AF: 0.443

Gnomad AMI AF: 0.532

Gnomad AMR AF: 0.468

Gnomad ASJ AF: 0.524

Gnomad EAS AF: 0.379

Gnomad SAS AF: 0.512

Gnomad FIN AF: 0.445

Gnomad MID AF: 0.535

Gnomad NFE AF: 0.548

Gnomad OTH AF: 0.522

GnomAD3 exomes AF: 0.492 AC: 123619 AN: 251124 Hom.: 31132 AF XY: 0.502 AC XY: 68124 AN XY: 135700

Gnomad AFR exome AF: 0.441

Gnomad AMR exome AF: 0.393

Gnomad ASJ exome AF: 0.513

Gnomad EAS exome AF: 0.370

Gnomad SAS exome AF: 0.514

Gnomad FIN exome AF: 0.449

Gnomad NFE exome AF: 0.549

Gnomad OTH exome AF: 0.520

GnomAD4 exome AF: 0.537 AC: 778534 AN: 1449652 Hom.: 211743 Cov.: 30 AF XY: 0.537 AC XY: 388041 AN XY: 721962

Gnomad4 AFR exome AF: 0.435

Gnomad4 AMR exome AF: 0.402

Gnomad4 ASJ exome AF: 0.513

Gnomad4 EAS exome AF: 0.384

Gnomad4 SAS exome AF: 0.516

Gnomad4 FIN exome AF: 0.455

Gnomad4 NFE exome AF: 0.558

Gnomad4 OTH exome AF: 0.529

GnomAD4 genome AF: 0.497 AC: 75471 AN: 151964 Hom.: 18953 Cov.: 32 AF XY: 0.492 AC XY: 36561 AN XY: 74254

Gnomad4 AFR AF: 0.444

Gnomad4 AMR AF: 0.467

Gnomad4 ASJ AF: 0.524

Gnomad4 EAS AF: 0.379

Gnomad4 SAS AF: 0.514

Gnomad4 FIN AF: 0.445

Gnomad4 NFE AF: 0.548

Gnomad4 OTH AF: 0.518

Alfa AF: 0.528 Hom.: 10113

Bravo AF: 0.494

Asia WGS AF: 0.402 AC: 1401 AN: 3478

EpiCase AF: 0.563

EpiControl AF: 0.571

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 03, 2012	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Norman-Roberts syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
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 12, 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:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 07, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	7.0
DANN	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000031
dbscSNV1_RF	Benign	0.0
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: rs607755; hg19: chr7-103389954; COSMIC: COSV58991817;