rs144387303

Positions:

chr7-103545189-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2BS1_Supporting

The NM_005045.4(RELN):c.6458G>A(p.Gly2153Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000409 in 1,613,974 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G2153G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

RELN
NM_005045.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 7.28

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 Uncertain_significance. Variant got 0 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.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00021 (32/152140) while in subpopulation AFR AF= 0.000748 (31/41418). AF 95% confidence interval is 0.000542. There are 0 homozygotes in gnomad4. There are 14 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RELN	NM_005045.4 linkuse as main transcript	c.6458G>A	p.Gly2153Asp	missense_variant	42/65	ENST00000428762.6
RELN	NM_173054.3 linkuse as main transcript	c.6458G>A	p.Gly2153Asp	missense_variant	42/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RELN	ENST00000428762.6 linkuse as main transcript	c.6458G>A	p.Gly2153Asp	missense_variant	42/65	5	NM_005045.4	P5	P78509-1

Frequencies

GnomAD3 genomes

AF:

0.000210

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000748

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000676

AC:

AN:

251398

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135860

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000233

AC:

AN:

1461834

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.000956

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.000210

AC:

AN:

152140

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.000748

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000418

Hom.:

Bravo

AF:

0.000234

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000906

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 22, 2018	- -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 07, 2023	Observed with a second RELN variant on the opposite allele (in trans) in a patient with autism in published literature; however, this patient also had a variant in an additional gene that could be contributing to the phenotype (PMID: 35668055); Identified in an individual with a neurodevelopmental disorder in published literature, but segregation and detailed clinical information were not provided (PMID: 33004838); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33004838, 35668055) -

Familial temporal lobe epilepsy 7

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Jun 19, 2020

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

0.0090

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

T;.;.

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Benign

0.045

MetaRNN

Uncertain

0.54

D;D;D

MetaSVM

Benign

-0.59

MutationAssessor

Benign

1.9

L;L;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-2.8

D;D;D

REVEL

Uncertain

0.41

Sift

Uncertain

0.0030

D;D;D

Sift4G

Uncertain

0.0050

D;D;D

Polyphen

0.99

D;D;.

Vest4

0.86

MVP

0.75

MPC

0.79

ClinPred

0.36

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.57

gMVP

0.89

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

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