7-103989356-TGCCGCCGCCGCCGCC-TGCCGCCGCCGCCGCCGCCGCCGCCGCC

Variant names:

• chr7-103989356-T-TGCCGCCGCCGCC
• rs55656324
• NM_005045.4:c.-12_-1dupGGCGGCGGCGGC

Variant summary

Our verdict is Benign. The variant received -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. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. 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
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• lissencephaly with cerebellar hypoplasia

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Norman-Roberts syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Illumina, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P, PanelApp Australia
• familial temporal lobe epilepsy 7

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autosomal dominant epilepsy with auditory features

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• ankylosing spondylitis

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• complex neurodevelopmental disorder

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 358424.
• 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 rank	MANE	Protein	UniProt
RELN	NM_005045.4	c.-12_-1dupGGCGGCGGCGGC		5_prime_UTR_variant	Exon 1 of 65	ENST00000428762.6	NP_005036.2
RELN	NM_173054.3	c.-12_-1dupGGCGGCGGCGGC		5_prime_UTR_variant	Exon 1 of 64		NP_774959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RELN	ENST00000428762.6	c.-12_-1dupGGCGGCGGCGGC		5_prime_UTR_variant	Exon 1 of 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

GnomAD2 exomes AF: 0.00146 AC: 93 AN: 63892 AF XY: 0.00178

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 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

African (AFR) AF: 0.0509 AC: 1252 AN: 24600

American (AMR) AF: 0.00481 AC: 102 AN: 21202

Ashkenazi Jewish (ASJ) AF: 0.00447 AC: 94 AN: 21032

East Asian (EAS) AF: 0.00459 AC: 124 AN: 27002

South Asian (SAS) AF: 0.0126 AC: 707 AN: 55966

European-Finnish (FIN) AF: 0.00405 AC: 153 AN: 37758

Middle Eastern (MID) AF: 0.0238 AC: 99 AN: 4154

European-Non Finnish (NFE) AF: 0.0104 AC: 10562 AN: 1014442

Other (OTH) AF: 0.0137 AC: 712 AN: 51978

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

African (AFR) AF: 0.0542 AC: 2184 AN: 40310

American (AMR) AF: 0.0171 AC: 258 AN: 15046

Ashkenazi Jewish (ASJ) AF: 0.00754 AC: 26 AN: 3446

East Asian (EAS) AF: 0.00383 AC: 18 AN: 4696

South Asian (SAS) AF: 0.0288 AC: 135 AN: 4692

European-Finnish (FIN) AF: 0.00567 AC: 57 AN: 10058

Middle Eastern (MID) AF: 0.0108 AC: 3 AN: 278

European-Non Finnish (NFE) AF: 0.0116 AC: 777 AN: 66866

Other (OTH) AF: 0.0316 AC: 65 AN: 2060

Alfa AF: 0.00263 Hom.: 609

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 24, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lissencephaly, Recessive Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Sep 28, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RELN-related disorder Benign:1

May 09, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.1
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs55656324; hg19: chr7-103629803;