rs200124755

Positions:

• chr7-103498074-T-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PP3_Moderate BP6 BS1 BS2

The NM_005045.4(RELN):​c.8843+3A>C variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000346 in 1,614,086 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00035 (2 hom.)
• Consequence: RELN NM_005045.4 splice_donor_region, intron
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:6 B:2
• Conservation: PhyloP100: 1.44

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]

SLC26A5-AS1 (HGNC:55680): (SLC26A5 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 7-103498074-T-G is Benign according to our data. Variant chr7-103498074-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 197969.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=6, Likely_benign=2}. Variant chr7-103498074-T-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000322 (49/152332) while in subpopulation SAS AF= 0.000622 (3/4826). AF 95% confidence interval is 0.000207. There are 0 homozygotes in gnomad4. There are 24 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RELN	NM_005045.4	c.8843+3A>C		splice_donor_region_variant, intron_variant		ENST00000428762.6
SLC26A5-AS1	NR_110141.1	n.1366-6330T>G		intron_variant, non_coding_transcript_variant
RELN	NM_173054.3	c.8843+3A>C		splice_donor_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RELN	ENST00000428762.6	c.8843+3A>C		splice_donor_region_variant, intron_variant		5	NM_005045.4	P5
SLC26A5-AS1	ENST00000422488.1	n.1366-6330T>G		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 49 AN: 152214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000518 AC: 130 AN: 251066 Hom.: 1 AF XY: 0.000560 AC XY: 76 AN XY: 135660

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000724

Gnomad ASJ exome AF: 0.00298

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000849

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.000309

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000349 AC: 510 AN: 1461754 Hom.: 2 Cov.: 34 AF XY: 0.000381 AC XY: 277 AN XY: 727186

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000738

Gnomad4 ASJ exome AF: 0.00230

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.000904

Gnomad4 FIN exome AF: 0.000243

Gnomad4 NFE exome AF: 0.000223

Gnomad4 OTH exome AF: 0.000497

GnomAD4 genome AF: 0.000322 AC: 49 AN: 152332 Hom.: 0 Cov.: 33 AF XY: 0.000322 AC XY: 24 AN XY: 74496

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000523 Hom.: 0

Bravo AF: 0.000378

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:6 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Norman-Roberts syndrome Uncertain:2

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 25, 2024	- -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 05, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	RELN: PP3, BS1 -

Childhood epilepsy with centrotemporal spikes Pathogenic:1

Pathogenic, no assertion criteria provided

case-control

Bioinformatics Core, Luxembourg Center for Systems Biomedicine

Jan 01, 2017

CAADphred>15 -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 17, 2018

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Familial temporal lobe epilepsy 7 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Aug 20, 2019

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3. -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Pathogenic	34
DANN	Benign	0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.88
SpliceAI score (max)		0.70		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.70		Position offset: 10

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs200124755; hg19: chr7-103138521;