7-103989356-TGCCGCCGCCGCCGCC-TGCCGCCGCCGCCGCCGCCGCCGCC

Variant names:

• chr7-103989356-T-TGCCGCCGCC
• rs55656324
• NM_005045.4:c.-9_-1dupGGCGGCGGC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_005045.4(RELN):​c.-9_-1dupGGCGGCGGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00678 in 1,407,470 control chromosomes in the GnomAD database, including 101 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (15 hom., cov: 0)
  • Exomes 𝑓: 0.0064 (86 hom.)
• Consequence: RELN NM_005045.4 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• 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 -16 ACMG points.

• BP6: Variant 7-103989356-T-TGCCGCCGCC is Benign according to our data. Variant chr7-103989356-T-TGCCGCCGCC is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 193298.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.01 (1483/148348) while in subpopulation AFR AF = 0.0177 (712/40308). AF 95% confidence interval is 0.0166. There are 15 homozygotes in GnomAd4. There are 745 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005045.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RELN	NM_005045.4	MANE Select	c.-9_-1dupGGCGGCGGC		5_prime_UTR	Exon 1 of 65	NP_005036.2
	RELN	NM_173054.3		c.-9_-1dupGGCGGCGGC		5_prime_UTR	Exon 1 of 64	NP_774959.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RELN	ENST00000428762.6	TSL:5 MANE Select	c.-9_-1dupGGCGGCGGC		5_prime_UTR	Exon 1 of 65	ENSP00000392423.1
	RELN	ENST00000473457.2	TSL:3	n.256_264dupGGCGGCGGC		non_coding_transcript_exon	Exon 1 of 21
	RELN	ENST00000679689.1		n.152_160dupGGCGGCGGC		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes AF: 0.00997 AC: 1478 AN: 148250 Hom.: 13 Cov.: 0

Gnomad AFR AF: 0.0176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00512

Gnomad ASJ AF: 0.00842

Gnomad EAS AF: 0.00721

Gnomad SAS AF: 0.00426

Gnomad FIN AF: 0.0133

Gnomad MID AF: 0.0101

Gnomad NFE AF: 0.00680

Gnomad OTH AF: 0.00982

GnomAD4 exome AF: 0.00640 AC: 8058 AN: 1259122 Hom.: 86 Cov.: 36 AF XY: 0.00617 AC XY: 3827 AN XY: 620182

African (AFR) AF: 0.0145 AC: 358 AN: 24630

American (AMR) AF: 0.00250 AC: 53 AN: 21230

Ashkenazi Jewish (ASJ) AF: 0.00447 AC: 94 AN: 21040

East Asian (EAS) AF: 0.00919 AC: 249 AN: 27106

South Asian (SAS) AF: 0.00260 AC: 146 AN: 56216

European-Finnish (FIN) AF: 0.0129 AC: 488 AN: 37756

Middle Eastern (MID) AF: 0.00554 AC: 23 AN: 4152

European-Non Finnish (NFE) AF: 0.00614 AC: 6229 AN: 1014952

Other (OTH) AF: 0.00803 AC: 418 AN: 52040

GnomAD4 genome AF: 0.0100 AC: 1483 AN: 148348 Hom.: 15 Cov.: 0 AF XY: 0.0103 AC XY: 745 AN XY: 72348

African (AFR) AF: 0.0177 AC: 712 AN: 40308

American (AMR) AF: 0.00512 AC: 77 AN: 15046

Ashkenazi Jewish (ASJ) AF: 0.00842 AC: 29 AN: 3446

East Asian (EAS) AF: 0.00724 AC: 34 AN: 4698

South Asian (SAS) AF: 0.00426 AC: 20 AN: 4692

European-Finnish (FIN) AF: 0.0133 AC: 134 AN: 10060

Middle Eastern (MID) AF: 0.00719 AC: 2 AN: 278

European-Non Finnish (NFE) AF: 0.00680 AC: 455 AN: 66868

Other (OTH) AF: 0.00971 AC: 20 AN: 2060

Alfa AF: 0.00619 Hom.: 609

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

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

Dec 05, 2014

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 25, 2017

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Nov 20, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

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;