rs78008536

chr7-103651754-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005045.4(RELN):c.1799C>T(p.Ser600Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.014 in 1,611,790 control chromosomes in the GnomAD database, including 208 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (12 hom., cov: 32)
  • Exomes 𝑓: 0.014 (196 hom.)
• Consequence: RELN NM_005045.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 7.63

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, RELN
• BP4: Computational evidence support a benign effect (MetaRNN=0.012332916).
• BP6: Variant 7-103651754-G-A is Benign according to our data. Variant chr7-103651754-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 95213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-103651754-G-A is described in Lovd as [Benign]. Variant chr7-103651754-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0105 (1595/152016) while in subpopulation NFE AF= 0.0167 (1132/67932). AF 95% confidence interval is 0.0159. There are 12 homozygotes in gnomad4. There are 818 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 12 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RELN	NM_005045.4	c.1799C>T	p.Ser600Phe	missense_variant	15/65	ENST00000428762.6
RELN	NM_173054.3	c.1799C>T	p.Ser600Phe	missense_variant	15/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RELN	ENST00000428762.6	c.1799C>T	p.Ser600Phe	missense_variant	15/65	5	NM_005045.4	P5

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 1595 AN: 151898 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00225

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00637

Gnomad ASJ AF: 0.00865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00831

Gnomad FIN AF: 0.0176

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0167

Gnomad OTH AF: 0.00766

GnomAD3 exomes AF: 0.0107 AC: 2687 AN: 250240 Hom.: 24 AF XY: 0.0111 AC XY: 1504 AN XY: 135280

Gnomad AFR exome AF: 0.00247

Gnomad AMR exome AF: 0.00346

Gnomad ASJ exome AF: 0.0101

Gnomad EAS exome AF: 0.0000547

Gnomad SAS exome AF: 0.00657

Gnomad FIN exome AF: 0.0173

Gnomad NFE exome AF: 0.0157

Gnomad OTH exome AF: 0.0115

GnomAD4 exome AF: 0.0143 AC: 20911 AN: 1459774 Hom.: 196 Cov.: 31 AF XY: 0.0141 AC XY: 10257 AN XY: 726264

Gnomad4 AFR exome AF: 0.00198

Gnomad4 AMR exome AF: 0.00370

Gnomad4 ASJ exome AF: 0.0108

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00774

Gnomad4 FIN exome AF: 0.0179

Gnomad4 NFE exome AF: 0.0163

Gnomad4 OTH exome AF: 0.0106

GnomAD4 genome AF: 0.0105 AC: 1595 AN: 152016 Hom.: 12 Cov.: 32 AF XY: 0.0110 AC XY: 818 AN XY: 74296

Gnomad4 AFR AF: 0.00224

Gnomad4 AMR AF: 0.00636

Gnomad4 ASJ AF: 0.00865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00832

Gnomad4 FIN AF: 0.0176

Gnomad4 NFE AF: 0.0167

Gnomad4 OTH AF: 0.00758

Alfa AF: 0.0143 Hom.: 10

Bravo AF: 0.00901

TwinsUK AF: 0.0148 AC: 55

ALSPAC AF: 0.0158 AC: 61

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.0151 AC: 130

ExAC AF: 0.0107 AC: 1297

Asia WGS AF: 0.00376 AC: 13 AN: 3476

EpiCase AF: 0.0149

EpiControl AF: 0.0131

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 15, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 06, 2013	- -

Norman-Roberts syndrome;C4225327:Familial temporal lobe epilepsy 7;C4551957:Epilepsy, familial temporal lobe, 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 29, 2021

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Norman-Roberts syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Oct 31, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.30
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.19	T;.;.
Eigen	Uncertain	0.60
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D
MetaRNN	Benign	0.012	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.7	D;D;D
REVEL	Benign	0.21
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		0.61	P;P;.
Vest4		0.33
MPC		0.50
ClinPred		0.013	T
GERP RS		5.8
Varity_R		0.42
gMVP		0.69

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: rs78008536; hg19: chr7-103292201;