rs200289289

chr7-103700935-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS1

The NM_005045.4(RELN):c.877G>A(p.Asp293Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000258 in 1,609,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: RELN NM_005045.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:3
• Conservation: PhyloP100: 5.46

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PP2: Missense variant where missense usually causes diseases, RELN
• BP4: Computational evidence support a benign effect (MetaRNN=0.060350657).
• BP6: Variant 7-103700935-C-T is Benign according to our data. Variant chr7-103700935-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 393143.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=4}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000329 (50/152092) while in subpopulation NFE AF= 0.000309 (21/67972). AF 95% confidence interval is 0.000207. There are 0 homozygotes in gnomad4. There are 30 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RELN	NM_005045.4	c.877G>A	p.Asp293Asn	missense_variant	9/65	ENST00000428762.6
RELN	NM_173054.3	c.877G>A	p.Asp293Asn	missense_variant	9/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RELN	ENST00000428762.6	c.877G>A	p.Asp293Asn	missense_variant	9/65	5	NM_005045.4	P5

Frequencies

GnomAD3 genomes AF: 0.000329 AC: 50 AN: 152092 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000450 AC: 113 AN: 251260 Hom.: 0 AF XY: 0.000442 AC XY: 60 AN XY: 135806

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00466

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000463

Gnomad NFE exome AF: 0.000387

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000251 AC: 366 AN: 1457718 Hom.: 0 Cov.: 29 AF XY: 0.000276 AC XY: 200 AN XY: 725406

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.00437

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000431

Gnomad4 NFE exome AF: 0.000152

Gnomad4 OTH exome AF: 0.000614

GnomAD4 genome AF: 0.000329 AC: 50 AN: 152092 Hom.: 0 Cov.: 32 AF XY: 0.000404 AC XY: 30 AN XY: 74304

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.00144

Alfa AF: 0.000640 Hom.: 0

Bravo AF: 0.000336

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000313 AC: 38

EpiCase AF: 0.000655

EpiControl AF: 0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2018	- -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 25, 2015

- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 20, 2021

Unlikely to be causative of RELN-related lateral temporal epilepsy (AD) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Norman-Roberts syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Norman-Roberts syndrome;C4225327:Familial temporal lobe epilepsy 7 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

RELN-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 01, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.071	T;.;.
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Benign	0.0092	T
MetaRNN	Benign	0.060	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.046
Sift	Benign	0.38	T;T;T
Sift4G	Uncertain	0.029	D;D;D
Polyphen		0.16	B;B;.
Vest4		0.80
MVP		0.58
MPC		0.18
ClinPred		0.019	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.14
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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

Other links and lift over

dbSNP: rs200289289; hg19: chr7-103341382;