7-103989356-TGCCGCCGCCGCCGCC-TGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCC

Position:

• chr7-103989356-TGCCGCCGCCGCCGCC-TGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCC

Variant summary

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

The NM_005045.4(RELN):​c.-18_-1dupGGCGGCGGCGGCGGCGGC 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 0.013 (41 hom., cov: 0)
  • Exomes 𝑓: 0.0011 (26 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: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 Benign. Variant got -9 ACMG points.

• BP6: Variant 7-103989356-T-TGCCGCCGCCGCCGCCGCC is Benign according to our data. Variant chr7-103989356-T-TGCCGCCGCCGCCGCCGCC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 358426.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0133 (1980/148346) while in subpopulation AFR AF= 0.0404 (1630/40300). AF 95% confidence interval is 0.0388. There are 41 homozygotes in gnomad4. There are 940 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 41 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RELN	NM_005045.4	c.-18_-1dupGGCGGCGGCGGCGGCGGC		5_prime_UTR_variant	1/65	ENST00000428762.6	NP_005036.2
RELN	NM_173054.3	c.-18_-1dupGGCGGCGGCGGCGGCGGC		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.-18_-1dupGGCGGCGGCGGCGGCGGC		5_prime_UTR_variant	1/65	5	NM_005045.4	ENSP00000392423.1

Frequencies

GnomAD3 genomes AF: 0.0133 AC: 1979 AN: 148248 Hom.: 42 Cov.: 0

Gnomad AFR AF: 0.0405

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00552

Gnomad ASJ AF: 0.00638

Gnomad EAS AF: 0.00891

Gnomad SAS AF: 0.00617

Gnomad FIN AF: 0.000398

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00215

Gnomad OTH AF: 0.0128

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00109 AC: 1372 AN: 1259028 Hom.: 26 Cov.: 36 AF XY: 0.00104 AC XY: 647 AN XY: 620162

Gnomad4 AFR exome AF: 0.0172

Gnomad4 AMR exome AF: 0.000707

Gnomad4 ASJ exome AF: 0.00153

Gnomad4 EAS exome AF: 0.00226

Gnomad4 SAS exome AF: 0.000924

Gnomad4 FIN exome AF: 0.000238

Gnomad4 NFE exome AF: 0.000675

Gnomad4 OTH exome AF: 0.00183

GnomAD4 genome AF: 0.0133 AC: 1980 AN: 148346 Hom.: 41 Cov.: 0 AF XY: 0.0130 AC XY: 940 AN XY: 72336

Gnomad4 AFR AF: 0.0404

Gnomad4 AMR AF: 0.00552

Gnomad4 ASJ AF: 0.00638

Gnomad4 EAS AF: 0.00894

Gnomad4 SAS AF: 0.00618

Gnomad4 FIN AF: 0.000398

Gnomad4 NFE AF: 0.00215

Gnomad4 OTH AF: 0.0126

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

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

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 18, 2019

- -

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;