7-103749507-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005045.4(RELN):c.578-3T>C variant causes a splice region, 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, intron

Scores

Splicing: ADA: 0.00003143

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.0830

Publications

22 publications found

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 Gene-Disease associations (from GenCC):

lissencephaly with cerebellar hypoplasia
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Norman-Roberts syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Illumina, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P, PanelApp Australia
familial temporal lobe epilepsy 7
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
autosomal dominant epilepsy with auditory features
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
ankylosing spondylitis
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
complex neurodevelopmental disorder
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

RELN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 95224.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.544 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005045.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RELN	NM_005045.4	MANE Select	c.578-3T>C		splice_region intron	N/A	NP_005036.2
	RELN	NM_173054.3		c.578-3T>C		splice_region intron	N/A	NP_774959.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
RELN	ENST00000428762.6	TSL:5 MANE Select	c.578-3T>C	splice_region intron	N/A	ENSP00000392423.1
RELN	ENST00000424685.3	TSL:5	c.578-3T>C	splice_region intron	N/A	ENSP00000388446.3
RELN	ENST00000343529.9	TSL:5	c.578-3T>C	splice_region intron	N/A	ENSP00000345694.5

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

GnomAD2 exomes

AF:

0.492

AC:

123619

AN:

251124

AF XY:

0.502

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 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

African (AFR)

AF:

0.435

AC:

14426

AN:

33190

American (AMR)

AF:

0.402

AC:

17987

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.513

AC:

13382

AN:

26076

East Asian (EAS)

AF:

0.384

AC:

15207

AN:

39588

South Asian (SAS)

AF:

0.516

AC:

44386

AN:

86050

European-Finnish (FIN)

AF:

0.455

AC:

24280

AN:

53370

Middle Eastern (MID)

AF:

0.549

AC:

3100

AN:

5648

European-Non Finnish (NFE)

AF:

0.558

AC:

614019

AN:

1101050

Other (OTH)

AF:

0.529

AC:

31747

AN:

59986

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

16094

32187

48281

64374

80468

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17062

34124

51186

68248

85310

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.497

AC:

75471

AN:

151964

Hom.:

18953

Cov.:

AF XY:

0.492

AC XY:

36561

AN XY:

74254

show subpopulations

African (AFR)

AF:

0.444

AC:

18400

AN:

41440

American (AMR)

AF:

0.467

AC:

7133

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.524

AC:

1815

AN:

3464

East Asian (EAS)

AF:

0.379

AC:

1956

AN:

5162

South Asian (SAS)

AF:

0.514

AC:

2476

AN:

4820

European-Finnish (FIN)

AF:

0.445

AC:

4701

AN:

10562

Middle Eastern (MID)

AF:

0.537

AC:

158

AN:

294

European-Non Finnish (NFE)

AF:

0.548

AC:

37254

AN:

67928

Other (OTH)

AF:

0.518

AC:

1093

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1932

3865

5797

7730

9662

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

686

1372

2058

2744

3430

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.526

Hom.:

10704

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

LINK: link

Submissions by phenotype

not specified

Benign:5

Jul 03, 2012

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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.

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Norman-Roberts syndrome

Benign:3

Jan 12, 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.

Nov 07, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not provided

Benign:3

May 07, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

7.0

(source)

DANN

Benign

0.77

PhyloP100

0.083

Mutation Taster

=94/6

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over