chr7-103989356-T-TGCCGCCGCCGCCGCCGCCGCC

Position:

• chr7-103989356-T-TGCCGCCGCCGCCGCCGCCGCC

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_005045.4(RELN):​c.-21_-1dupGGCGGCGGCGGCGGCGGCGGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (6 hom., cov: 0)
  • Exomes 𝑓: 0.0012 (32 hom.)
  • Failed GnomAD Quality Control
• Consequence: RELN NM_005045.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 B:1
• 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 Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00407 (604/148366) while in subpopulation EAS AF= 0.0292 (137/4696). AF 95% confidence interval is 0.0252. There are 6 homozygotes in gnomad4. There are 295 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RELN	NM_005045.4	c.-21_-1dupGGCGGCGGCGGCGGCGGCGGC		5_prime_UTR_variant	1/65	ENST00000428762.6	NP_005036.2
RELN	NM_173054.3	c.-21_-1dupGGCGGCGGCGGCGGCGGCGGC		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.-21_-1dupGGCGGCGGCGGCGGCGGCGGC		5_prime_UTR_variant	1/65	5	NM_005045.4	ENSP00000392423.1

Frequencies

GnomAD3 genomes AF: 0.00405 AC: 601 AN: 148268 Hom.: 6 Cov.: 0

Gnomad AFR AF: 0.00313

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00160

Gnomad ASJ AF: 0.000871

Gnomad EAS AF: 0.0293

Gnomad SAS AF: 0.00490

Gnomad FIN AF: 0.000596

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00414

Gnomad OTH AF: 0.00196

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00118 AC: 1487 AN: 1259304 Hom.: 32 Cov.: 36 AF XY: 0.00111 AC XY: 688 AN XY: 620268

Gnomad4 AFR exome AF: 0.000892

Gnomad4 AMR exome AF: 0.000377

Gnomad4 ASJ exome AF: 0.000285

Gnomad4 EAS exome AF: 0.00323

Gnomad4 SAS exome AF: 0.000764

Gnomad4 FIN exome AF: 0.000132

Gnomad4 NFE exome AF: 0.00123

Gnomad4 OTH exome AF: 0.00133

GnomAD4 genome AF: 0.00407 AC: 604 AN: 148366 Hom.: 6 Cov.: 0 AF XY: 0.00408 AC XY: 295 AN XY: 72352

Gnomad4 AFR AF: 0.00325

Gnomad4 AMR AF: 0.00153

Gnomad4 ASJ AF: 0.000871

Gnomad4 EAS AF: 0.0292

Gnomad4 SAS AF: 0.00490

Gnomad4 FIN AF: 0.000596

Gnomad4 NFE AF: 0.00414

Gnomad4 OTH AF: 0.00194

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 12, 2016

- -

Lissencephaly, Recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

RELN-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 24, 2023

This variant is classified as likely 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;