rs607755

Positions:

chr7-103749507-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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:11

Conservation

PhyloP100: 0.0830

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	UniProt
RELN	NM_005045.4 linkuse as main transcript	c.578-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000428762.6
RELN	NM_173054.3 linkuse as main transcript	c.578-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RELN	ENST00000428762.6 linkuse as main transcript	c.578-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_005045.4	P5	P78509-1

Frequencies

GnomAD3 genomes

AF:

0.497

AC:

75403

AN:

151846

Hom.:

18925

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.537

AC XY:

388041

AN XY:

721962

show subpopulations

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.:

AF XY:

0.492

AC XY:

36561

AN XY:

74254

show subpopulations

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:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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 DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	- -

Norman-Roberts syndrome

Benign:3

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 07, 2018	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

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

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