rs362801

Positions:

• chr7-103566767-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005045.4(RELN):​c.4589-8T>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00337 in 1,613,672 control chromosomes in the GnomAD database, including 138 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (69 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (69 hom.)
• Consequence: RELN NM_005045.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.1039
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.474

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 7-103566767-A-C is Benign according to our data. Variant chr7-103566767-A-C is described in ClinVar as [Benign]. Clinvar id is 130122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-103566767-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0589 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RELN	NM_005045.4	c.4589-8T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000428762.6	NP_005036.2
RELN	NM_173054.3	c.4589-8T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_774959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RELN	ENST00000428762.6	c.4589-8T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_005045.4	ENSP00000392423	P5

Frequencies

GnomAD3 genomes AF: 0.0177 AC: 2689 AN: 152232 Hom.: 69 Cov.: 32

Gnomad AFR AF: 0.0610

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00543

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.0196

GnomAD3 exomes AF: 0.00449 AC: 1128 AN: 251130 Hom.: 29 AF XY: 0.00322 AC XY: 437 AN XY: 135710

Gnomad AFR exome AF: 0.0609

Gnomad AMR exome AF: 0.00249

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000326

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00188 AC: 2745 AN: 1461322 Hom.: 69 Cov.: 31 AF XY: 0.00153 AC XY: 1114 AN XY: 727018

Gnomad4 AFR exome AF: 0.0627

Gnomad4 AMR exome AF: 0.00288

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000215

Gnomad4 OTH exome AF: 0.00408

GnomAD4 genome AF: 0.0177 AC: 2691 AN: 152350 Hom.: 69 Cov.: 32 AF XY: 0.0165 AC XY: 1227 AN XY: 74498

Gnomad4 AFR AF: 0.0609

Gnomad4 AMR AF: 0.00542

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000470

Gnomad4 OTH AF: 0.0194

Alfa AF: 0.00824 Hom.: 15

Bravo AF: 0.0198

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 04, 2015	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 15, 2013

- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	13
DANN	Benign	0.83

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.10
dbscSNV1_RF	Benign	0.23
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.25		Position offset: 32

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

Publications

LitVar

Other links and lift over

dbSNP: rs362801; hg19: chr7-103207214;