rs362719

Variant names:

• chr7-103545430-C-A
• rs362719
• NM_005045.4:c.6303-86G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005045.4(RELN):​c.6303-86G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.243 in 889,372 control chromosomes in the GnomAD database, including 32,776 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (10356 hom., cov: 32)
  • Exomes 𝑓: 0.23 (22420 hom.)
• Consequence: RELN NM_005045.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.90
• Publications: 23 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 7-103545430-C-A is Benign according to our data. Variant chr7-103545430-C-A is described in ClinVar as Benign. ClinVar VariationId is 674180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.594 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RELN	NM_005045.4	c.6303-86G>T		intron_variant	Intron 41 of 64	ENST00000428762.6	NP_005036.2
RELN	NM_173054.3	c.6303-86G>T		intron_variant	Intron 41 of 63		NP_774959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RELN	ENST00000428762.6	c.6303-86G>T		intron_variant	Intron 41 of 64	5	NM_005045.4	ENSP00000392423.1

Frequencies

GnomAD3 genomes AF: 0.320 AC: 48605 AN: 151920 Hom.: 10325 Cov.: 32

Gnomad AFR AF: 0.600

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.283

Gnomad ASJ AF: 0.203

Gnomad EAS AF: 0.368

Gnomad SAS AF: 0.393

Gnomad FIN AF: 0.215

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.176

Gnomad OTH AF: 0.289

GnomAD4 exome AF: 0.227 AC: 167614 AN: 737334 Hom.: 22420 AF XY: 0.231 AC XY: 90012 AN XY: 390064

African (AFR) AF: 0.600 AC: 11644 AN: 19392

American (AMR) AF: 0.295 AC: 10854 AN: 36838

Ashkenazi Jewish (ASJ) AF: 0.212 AC: 4491 AN: 21156

East Asian (EAS) AF: 0.344 AC: 11661 AN: 33894

South Asian (SAS) AF: 0.375 AC: 25423 AN: 67878

European-Finnish (FIN) AF: 0.215 AC: 9101 AN: 42338

Middle Eastern (MID) AF: 0.165 AC: 695 AN: 4218

European-Non Finnish (NFE) AF: 0.178 AC: 84637 AN: 474736

Other (OTH) AF: 0.247 AC: 9108 AN: 36884

GnomAD4 genome AF: 0.320 AC: 48706 AN: 152038 Hom.: 10356 Cov.: 32 AF XY: 0.324 AC XY: 24072 AN XY: 74302

African (AFR) AF: 0.600 AC: 24876 AN: 41444

American (AMR) AF: 0.283 AC: 4330 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.203 AC: 706 AN: 3470

East Asian (EAS) AF: 0.368 AC: 1901 AN: 5168

South Asian (SAS) AF: 0.394 AC: 1897 AN: 4812

European-Finnish (FIN) AF: 0.215 AC: 2272 AN: 10580

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.176 AC: 11960 AN: 67968

Other (OTH) AF: 0.294 AC: 620 AN: 2108

Alfa AF: 0.217 Hom.: 18932

Bravo AF: 0.333

Asia WGS AF: 0.413 AC: 1436 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.047
DANN	Benign	0.28
PhyloP100		-1.9
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs362719; hg19: chr7-103185877;