rs114807343

Positions:

chr7-103553706-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_005045.4(RELN):c.5923G>A(p.Gly1975Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000501 in 1,614,100 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0028 ( 4 hom., cov: 32)

Exomes 𝑓: 0.00026 ( 2 hom. )

Consequence

RELN
NM_005045.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 7.57

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:

RELN (HGNC:):

RELN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RELN. . Gene score misZ 2.2497 (greater than the threshold 3.09). Trascript score misZ 4.2638 (greater than threshold 3.09). GenCC has associacion of gene with ankylosing spondylitis, lissencephaly with cerebellar hypoplasia, Norman-Roberts syndrome, complex neurodevelopmental disorder, autosomal dominant epilepsy with auditory features, familial temporal lobe epilepsy 7.

BP4

Computational evidence support a benign effect (MetaRNN=0.014485866).

BP6

Variant 7-103553706-C-T is Benign according to our data. Variant chr7-103553706-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 167581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-103553706-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00279 (425/152272) while in subpopulation AFR AF= 0.0096 (399/41548). AF 95% confidence interval is 0.00883. There are 4 homozygotes in gnomad4. There are 200 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RELN	NM_005045.4 linkuse as main transcript	c.5923G>A	p.Gly1975Ser	missense_variant	39/65	ENST00000428762.6	NP_005036.2	P78509-1
RELN	NM_173054.3 linkuse as main transcript	c.5923G>A	p.Gly1975Ser	missense_variant	39/64		NP_774959.1	P78509-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RELN	ENST00000428762.6 linkuse as main transcript	c.5923G>A	p.Gly1975Ser	missense_variant	39/65	5	NM_005045.4	ENSP00000392423.1		P78509-1

Frequencies

GnomAD3 genomes

AF:

0.00281

AC:

428

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00963

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00151

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.000669

AC:

168

AN:

251182

Hom.:

AF XY:

0.000567

AC XY:

AN XY:

135764

show subpopulations

Gnomad AFR exome

AF:

0.00886

Gnomad AMR exome

AF:

0.000492

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000262

AC:

383

AN:

1461828

Hom.:

Cov.:

AF XY:

0.000210

AC XY:

153

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.00896

Gnomad4 AMR exome

AF:

0.000693

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.000695

GnomAD4 genome

AF:

0.00279

AC:

425

AN:

152272

Hom.:

Cov.:

AF XY:

0.00269

AC XY:

200

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.00960

Gnomad4 AMR

AF:

0.00144

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.000486

Hom.:

Bravo

AF:

0.00320

ESP6500AA

AF:

0.00794

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000807

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 13, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 13, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	RELN: BS2 -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Feb 07, 2014

- -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Norman-Roberts syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Apr 04, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Uncertain

0.090

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

T;.;.

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Benign

0.037

MetaRNN

Benign

0.014

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

L;L;.

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-2.3

N;N;N

REVEL

Uncertain

0.37

Sift

Benign

0.033

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

0.98

D;D;.

Vest4

0.92

MVP

0.81

MPC

0.50

ClinPred

0.016

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.34

gMVP

0.63

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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