rs79471015

chr7-103833594-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_005045.4(RELN):c.416C>G(p.Thr139Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00312 in 1,613,960 control chromosomes in the GnomAD database, including 154 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T139A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0037 (19 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (135 hom.)
• Consequence: RELN NM_005045.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 5.70

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=0.0037332475).
• BP6: Variant 7-103833594-G-C is Benign according to our data. Variant chr7-103833594-G-C is described in ClinVar as [Benign]. Clinvar id is 130121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0554 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RELN	NM_005045.4	c.416C>G	p.Thr139Ser	missense_variant	3/65	ENST00000428762.6
RELN	NM_173054.3	c.416C>G	p.Thr139Ser	missense_variant	3/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RELN	ENST00000428762.6	c.416C>G	p.Thr139Ser	missense_variant	3/65	5	NM_005045.4	P5

Frequencies

GnomAD3 genomes AF: 0.00371 AC: 565 AN: 152170 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0118

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.0610

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00833 AC: 2094 AN: 251248 Hom.: 49 AF XY: 0.00693 AC XY: 941 AN XY: 135776

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.0242

Gnomad ASJ exome AF: 0.000695

Gnomad EAS exome AF: 0.0630

Gnomad SAS exome AF: 0.00101

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000308

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00306 AC: 4476 AN: 1461672 Hom.: 135 Cov.: 31 AF XY: 0.00290 AC XY: 2110 AN XY: 727164

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.0224

Gnomad4 ASJ exome AF: 0.000957

Gnomad4 EAS exome AF: 0.0732

Gnomad4 SAS exome AF: 0.000916

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000263

Gnomad4 OTH exome AF: 0.00253

GnomAD4 genome AF: 0.00370 AC: 563 AN: 152288 Hom.: 19 Cov.: 32 AF XY: 0.00389 AC XY: 290 AN XY: 74462

Gnomad4 AFR AF: 0.000650

Gnomad4 AMR AF: 0.0118

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.0610

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00272 Hom.: 9

Bravo AF: 0.00516

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00746 AC: 906

Asia WGS AF: 0.0240 AC: 82 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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	GeneDx	Mar 30, 2016	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)	Mar 26, 2015	- -

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

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 15, 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 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.51
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.060	T;.;.
Eigen	Benign	-0.042
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.71	T;T;T
MetaRNN	Benign	0.0037	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.40	N;N;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.83	N;N;N
REVEL	Benign	0.074
Sift	Benign	0.099	T;T;T
Sift4G	Benign	0.49	T;T;T
Polyphen		0.074	B;B;.
Vest4		0.35
MutPred		0.61		Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);
MVP		0.34
MPC		0.21
ClinPred		0.012	T
GERP RS		5.3
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.7
Varity_R		0.16
gMVP		0.29

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: rs79471015; hg19: chr7-103474041; COSMIC: COSV58991896;