rs115913736

chr7-103565332-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_005045.4(RELN):c.5156C>T(p.Ser1719Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00685 in 1,614,100 control chromosomes in the GnomAD database, including 70 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S1719S) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0054 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0070 (63 hom.)
• Consequence: RELN NM_005045.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:12
• Conservation: PhyloP100: 9.26

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 -12 ACMG points.

• PP2: Missense variant where missense usually causes diseases, RELN
• BP4: Computational evidence support a benign effect (MetaRNN=0.008295119).
• BP6: Variant 7-103565332-G-A is Benign according to our data. Variant chr7-103565332-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 130126.We mark this variant Likely_benign, oryginal submissions are: {Benign=7, Likely_benign=2, Uncertain_significance=1}. Variant chr7-103565332-G-A is described in Lovd as [Likely_benign]. Variant chr7-103565332-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00535 (815/152288) while in subpopulation SAS AF= 0.0137 (66/4820). AF 95% confidence interval is 0.011. There are 7 homozygotes in gnomad4. There are 407 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RELN	NM_005045.4	c.5156C>T	p.Ser1719Leu	missense_variant	34/65	ENST00000428762.6
RELN	NM_173054.3	c.5156C>T	p.Ser1719Leu	missense_variant	34/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RELN	ENST00000428762.6	c.5156C>T	p.Ser1719Leu	missense_variant	34/65	5	NM_005045.4	P5

Frequencies

GnomAD3 genomes AF: 0.00536 AC: 815 AN: 152170 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.0308

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0137

Gnomad FIN AF: 0.00783

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00647

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00660 AC: 1660 AN: 251400 Hom.: 12 AF XY: 0.00709 AC XY: 963 AN XY: 135860

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00231

Gnomad ASJ exome AF: 0.0251

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00987

Gnomad FIN exome AF: 0.00711

Gnomad NFE exome AF: 0.00710

Gnomad OTH exome AF: 0.00701

GnomAD4 exome AF: 0.00701 AC: 10244 AN: 1461812 Hom.: 63 Cov.: 33 AF XY: 0.00718 AC XY: 5225 AN XY: 727216

Gnomad4 AFR exome AF: 0.00117

Gnomad4 AMR exome AF: 0.00219

Gnomad4 ASJ exome AF: 0.0253

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0105

Gnomad4 FIN exome AF: 0.00730

Gnomad4 NFE exome AF: 0.00696

Gnomad4 OTH exome AF: 0.00649

GnomAD4 genome AF: 0.00535 AC: 815 AN: 152288 Hom.: 7 Cov.: 32 AF XY: 0.00547 AC XY: 407 AN XY: 74462

Gnomad4 AFR AF: 0.00137

Gnomad4 AMR AF: 0.00346

Gnomad4 ASJ AF: 0.0308

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0137

Gnomad4 FIN AF: 0.00783

Gnomad4 NFE AF: 0.00647

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00722 Hom.: 6

Bravo AF: 0.00415

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00814 AC: 70

ExAC AF: 0.00670 AC: 814

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00709

EpiControl AF: 0.00729

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 25, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 12, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	RELN: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 12, 2020	This variant is associated with the following publications: (PMID: 14515139, 29706646) -

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 28, 2014	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 12, 2014	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Norman-Roberts syndrome Uncertain:1 Benign:1

Benign, 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Uncertain significance, criteria provided, single submitter	research	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	Sep 01, 2017	this variant was indentified in an individual with malformations of cortical development -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

RELN-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 17, 2019

This variant is classified as 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	0.17
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.080
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.14	T;.;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D
MetaRNN	Benign	0.0083	T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.2	M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.2	N;N;N
REVEL	Uncertain	0.34
Sift	Benign	0.16	T;T;T
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.87
MVP		0.77
MPC		0.65
ClinPred		0.016	T
GERP RS		5.2
Varity_R		0.15
gMVP		0.81

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

Other links and lift over

dbSNP: rs115913736; hg19: chr7-103205779; COSMIC: COSV104640391;