7-103989356-TGCCGCCGCCGCCGCC-TGCCGCCGCCGCCGCCGCCGCCGCCGCC

Position:

• chr7-103989356-TGCCGCCGCCGCCGCC-TGCCGCCGCCGCCGCCGCCGCCGCCGCC

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BA1

The NM_005045.4(RELN):​c.-12_-1dupGGCGGCGGCGGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.024 (71 hom., cov: 0)
  • Exomes 𝑓: 0.011 (239 hom.)
  • Failed GnomAD Quality Control
• Consequence: RELN NM_005045.4 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 2.06

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]

RELN (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP6: Variant 7-103989356-T-TGCCGCCGCCGCC is Benign according to our data. Variant chr7-103989356-T-TGCCGCCGCCGCC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 358424.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2}.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0523 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RELN	NM_005045.4	c.-12_-1dupGGCGGCGGCGGC		5_prime_UTR_variant	1/65	ENST00000428762.6	NP_005036.2
RELN	NM_173054.3	c.-12_-1dupGGCGGCGGCGGC		5_prime_UTR_variant	1/64		NP_774959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RELN	ENST00000428762.6	c.-12_-1dupGGCGGCGGCGGC		5_prime_UTR_variant	1/65	5	NM_005045.4	ENSP00000392423.1

Frequencies

GnomAD3 genomes AF: 0.0241 AC: 3573 AN: 148246 Hom.: 71 Cov.: 0

Gnomad AFR AF: 0.0542

Gnomad AMI AF: 0.0617

Gnomad AMR AF: 0.0172

Gnomad ASJ AF: 0.00754

Gnomad EAS AF: 0.00382

Gnomad SAS AF: 0.0287

Gnomad FIN AF: 0.00567

Gnomad MID AF: 0.0101

Gnomad NFE AF: 0.0116

Gnomad OTH AF: 0.0319

GnomAD3 exomes AF: 0.00146 AC: 93 AN: 63892 Hom.: 6 AF XY: 0.00178 AC XY: 66 AN XY: 37010

Gnomad AFR exome AF: 0.000613

Gnomad AMR exome AF: 0.000664

Gnomad ASJ exome AF: 0.000999

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00329

Gnomad FIN exome AF: 0.00153

Gnomad NFE exome AF: 0.00143

Gnomad OTH exome AF: 0.000597

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0110 AC: 13805 AN: 1258134 Hom.: 239 Cov.: 36 AF XY: 0.0109 AC XY: 6725 AN XY: 619642

Gnomad4 AFR exome AF: 0.0509

Gnomad4 AMR exome AF: 0.00481

Gnomad4 ASJ exome AF: 0.00447

Gnomad4 EAS exome AF: 0.00459

Gnomad4 SAS exome AF: 0.0126

Gnomad4 FIN exome AF: 0.00405

Gnomad4 NFE exome AF: 0.0104

Gnomad4 OTH exome AF: 0.0137

GnomAD4 genome AF: 0.0241 AC: 3578 AN: 148344 Hom.: 71 Cov.: 0 AF XY: 0.0243 AC XY: 1758 AN XY: 72342

Gnomad4 AFR AF: 0.0542

Gnomad4 AMR AF: 0.0171

Gnomad4 ASJ AF: 0.00754

Gnomad4 EAS AF: 0.00383

Gnomad4 SAS AF: 0.0288

Gnomad4 FIN AF: 0.00567

Gnomad4 NFE AF: 0.0116

Gnomad4 OTH AF: 0.0316

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Aug 24, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Lissencephaly, Recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 28, 2015

- -

RELN-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 09, 2019

This variant is classified as 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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs55656324; hg19: chr7-103629803;