7-103989356-TGCCGCCGCCGCCGCC-TGCCGCCGCC

Position:

• chr7-103989356-TGCCGCCGCCGCCGCC-TGCCGCCGCC

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_005045.4(RELN):​c.-6_-1delGGCGGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000358 in 1,408,074 control chromosomes in the GnomAD database, including 22 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00027 (22 hom.)
• Consequence: RELN NM_005045.4 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• 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-TGCCGCC-T is Benign according to our data. Variant chr7-103989356-TGCCGCC-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 358430.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}. Variant chr7-103989356-TGCCGCC-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00106 (158/148366) while in subpopulation AFR AF= 0.003 (121/40318). AF 95% confidence interval is 0.00257. There are 0 homozygotes in gnomad4. There are 82 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 22 AD,AR gene

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.00105 AC: 156 AN: 148268 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00301

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00297

Gnomad SAS AF: 0.000639

Gnomad FIN AF: 0.000994

Gnomad MID AF: 0.00338

Gnomad NFE AF: 0.000105

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000275 AC: 346 AN: 1259708 Hom.: 22 AF XY: 0.000250 AC XY: 155 AN XY: 620506

Gnomad4 AFR exome AF: 0.00373

Gnomad4 AMR exome AF: 0.000424

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00299

Gnomad4 SAS exome AF: 0.000462

Gnomad4 FIN exome AF: 0.000608

Gnomad4 NFE exome AF: 0.0000926

Gnomad4 OTH exome AF: 0.000403

GnomAD4 genome AF: 0.00106 AC: 158 AN: 148366 Hom.: 0 Cov.: 0 AF XY: 0.00113 AC XY: 82 AN XY: 72354

Gnomad4 AFR AF: 0.00300

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00298

Gnomad4 SAS AF: 0.000639

Gnomad4 FIN AF: 0.000994

Gnomad4 NFE AF: 0.000105

Gnomad4 OTH AF: 0.000971

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Lissencephaly, Recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 17, 2021

- -

RELN-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 08, 2024

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;