7-103989356-TGCCGCCGCCGCCGCC-TGCCGCCGCCGCC

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_005045.4(RELN):c.-3_-1delGGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00167 in 1,396,900 control chromosomes in the GnomAD database, including 35 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0016 ( 1 hom., cov: 0)

Exomes 𝑓: 0.0017 ( 34 hom. )

Consequence

RELN
NM_005045.4 5_prime_UTR

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 2.06

Publications

2 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 -9 ACMG points.

BP6

Variant 7-103989356-TGCC-T is Benign according to our data. Variant chr7-103989356-TGCC-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 358429.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00159 (236/148362) while in subpopulation EAS AF = 0.00404 (19/4698). AF 95% confidence interval is 0.00265. There are 1 homozygotes in GnomAd4. There are 120 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 34 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RELN	NM_005045.4 link	c.-3_-1delGGC		5_prime_UTR_variant	Exon 1 of 65	ENST00000428762.6	NP_005036.2
RELN	NM_173054.3 link	c.-3_-1delGGC		5_prime_UTR_variant	Exon 1 of 64		NP_774959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RELN	ENST00000428762.6 link	c.-3_-1delGGC		5_prime_UTR_variant	Exon 1 of 65	5	NM_005045.4	ENSP00000392423.1

Frequencies

GnomAD3 genomes

AF:

0.00158

AC:

234

AN:

148264

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00308

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00220

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00403

Gnomad SAS

AF:

0.00149

Gnomad FIN

AF:

0.000298

Gnomad MID

AF:

0.00676

Gnomad NFE

AF:

0.000643

Gnomad OTH

AF:

0.00147

GnomAD2 exomes

AF:

0.0113

AC:

720

AN:

63892

AF XY:

0.00989

show subpopulations

Gnomad AFR exome

AF:

0.0245

Gnomad AMR exome

AF:

0.0187

Gnomad ASJ exome

AF:

0.0115

Gnomad EAS exome

AF:

0.0303

Gnomad FIN exome

AF:

0.00695

Gnomad NFE exome

AF:

0.00926

Gnomad OTH exome

AF:

0.0149

GnomAD4 exome

AF:

0.00168

AC:

2097

AN:

1248538

Hom.:

AF XY:

0.00170

AC XY:

1043

AN XY:

614850

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00466

AC:

114

AN:

24482

American (AMR)

AF:

0.00711

AC:

146

AN:

20548

Ashkenazi Jewish (ASJ)

AF:

0.00338

AC:

AN:

20688

East Asian (EAS)

AF:

0.00296

AC:

AN:

27014

South Asian (SAS)

AF:

0.00267

AC:

148

AN:

55498

European-Finnish (FIN)

AF:

0.00132

AC:

AN:

37208

Middle Eastern (MID)

AF:

0.00145

AC:

AN:

4126

European-Non Finnish (NFE)

AF:

0.00134

AC:

1352

AN:

1007430

Other (OTH)

AF:

0.00256

AC:

132

AN:

51544

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.364

Heterozygous variant carriers

173

347

520

694

867

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

176

220

<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:

0.00159

AC:

236

AN:

148362

Hom.:

Cov.:

AF XY:

0.00166

AC XY:

120

AN XY:

72350

show subpopulations

African (AFR)

AF:

0.00308

AC:

124

AN:

40316

American (AMR)

AF:

0.00219

AC:

AN:

15048

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3446

East Asian (EAS)

AF:

0.00404

AC:

AN:

4698

South Asian (SAS)

AF:

0.00128

AC:

AN:

4692

European-Finnish (FIN)

AF:

0.000298

AC:

AN:

10060

Middle Eastern (MID)

AF:

0.00360

AC:

AN:

278

European-Non Finnish (NFE)

AF:

0.000643

AC:

AN:

66872

Other (OTH)

AF:

0.00340

AC:

AN:

2060

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

609

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RELN: BP4, BS2 -

Lissencephaly, Recessive

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.1

Mutation Taster

=299/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over