NM_005045.4:c.473+20415A>G

Variant names:

• chr7-103813122-T-C
• rs39335
• NM_005045.4:c.473+20415A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005045.4(RELN):​c.473+20415A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.204 in 152,188 control chromosomes in the GnomAD database, including 3,576 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.20 (3576 hom., cov: 32)
• Consequence: RELN NM_005045.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.22
• Publications: 6 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.295 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RELN	NM_005045.4	c.473+20415A>G		intron_variant	Intron 3 of 64	ENST00000428762.6	NP_005036.2
RELN	NM_173054.3	c.473+20415A>G		intron_variant	Intron 3 of 63		NP_774959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RELN	ENST00000428762.6	c.473+20415A>G		intron_variant	Intron 3 of 64	5	NM_005045.4	ENSP00000392423.1

Frequencies

GnomAD3 genomes AF: 0.204 AC: 31078 AN: 152070 Hom.: 3580 Cov.: 32

Gnomad AFR AF: 0.300

Gnomad AMI AF: 0.207

Gnomad AMR AF: 0.228

Gnomad ASJ AF: 0.212

Gnomad EAS AF: 0.0531

Gnomad SAS AF: 0.104

Gnomad FIN AF: 0.241

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.152

Gnomad OTH AF: 0.233

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.204 AC: 31077 AN: 152188 Hom.: 3576 Cov.: 32 AF XY: 0.205 AC XY: 15231 AN XY: 74406

African (AFR) AF: 0.300 AC: 12446 AN: 41500

American (AMR) AF: 0.227 AC: 3473 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.212 AC: 736 AN: 3470

East Asian (EAS) AF: 0.0530 AC: 275 AN: 5184

South Asian (SAS) AF: 0.103 AC: 497 AN: 4830

European-Finnish (FIN) AF: 0.241 AC: 2555 AN: 10598

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.152 AC: 10332 AN: 68006

Other (OTH) AF: 0.229 AC: 484 AN: 2112

Alfa AF: 0.173 Hom.: 7587

Bravo AF: 0.215

Asia WGS AF: 0.0930 AC: 326 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.29
DANN	Benign	0.38
PhyloP100		-1.2
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: rs39335; hg19: chr7-103453569;