rs143213152

chr7-103574195-C-T

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.4408G>A(p.Val1470Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00337 in 1,614,192 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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 0.0023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (10 hom.)
• Consequence: RELN NM_005045.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 2.91

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=0.009001464).
• BP6: Variant 7-103574195-C-T is Benign according to our data. Variant chr7-103574195-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 167585.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=6, Uncertain_significance=1}. Variant chr7-103574195-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00232 (353/152320) while in subpopulation NFE AF= 0.00392 (267/68040). AF 95% confidence interval is 0.00354. There are 0 homozygotes in gnomad4. There are 150 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RELN	NM_005045.4	c.4408G>A	p.Val1470Ile	missense_variant	30/65	ENST00000428762.6
RELN	NM_173054.3	c.4408G>A	p.Val1470Ile	missense_variant	30/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RELN	ENST00000428762.6	c.4408G>A	p.Val1470Ile	missense_variant	30/65	5	NM_005045.4	P5

Frequencies

GnomAD3 genomes AF: 0.00232 AC: 353 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00392

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00248 AC: 624 AN: 251442 Hom.: 5 AF XY: 0.00249 AC XY: 339 AN XY: 135900

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.00198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00206

Gnomad FIN exome AF: 0.00134

Gnomad NFE exome AF: 0.00390

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00348 AC: 5091 AN: 1461872 Hom.: 10 Cov.: 32 AF XY: 0.00336 AC XY: 2446 AN XY: 727240

Gnomad4 AFR exome AF: 0.000717

Gnomad4 AMR exome AF: 0.00119

Gnomad4 ASJ exome AF: 0.00142

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00177

Gnomad4 FIN exome AF: 0.00142

Gnomad4 NFE exome AF: 0.00407

Gnomad4 OTH exome AF: 0.00366

GnomAD4 genome AF: 0.00232 AC: 353 AN: 152320 Hom.: 0 Cov.: 32 AF XY: 0.00201 AC XY: 150 AN XY: 74482

Gnomad4 AFR AF: 0.000794

Gnomad4 AMR AF: 0.00176

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.000660

Gnomad4 NFE AF: 0.00392

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00361 Hom.: 1

Bravo AF: 0.00235

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00314 AC: 27

ExAC AF: 0.00265 AC: 322

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00431

EpiControl AF: 0.00344

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 31, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	RELN: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 22, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 27, 2017	- -

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. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 28, 2019

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	0.075
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	17
Dann	Uncertain	0.98
DEOGEN2	Benign	0.063	T;.;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.84	T;T;T
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.0090	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.21	N;N;.
MutationTaster	Benign	0.93	D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.10	N;N;N
REVEL	Benign	0.019
Sift	Benign	0.57	T;T;T
Sift4G	Benign	0.82	T;T;T
Polyphen		0.080	B;B;.
Vest4		0.21
MVP		0.24
MPC		0.14
ClinPred		0.012	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.066
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs143213152; hg19: chr7-103214642; COSMIC: COSV105213993;