NM_005045.4:c.473+7486C>T

Variant names:

• chr7-103826051-G-A
• rs39347
• NM_005045.4:c.473+7486C>T

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+7486C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.405 in 151,742 control chromosomes in the GnomAD database, including 12,664 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 0.40 (12664 hom., cov: 30)
• Consequence: RELN NM_005045.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.218
• Publications: 0 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=-0.94).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.456 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RELN	NM_005045.4	c.473+7486C>T		intron_variant	Intron 3 of 64	ENST00000428762.6	NP_005036.2
RELN	NM_173054.3	c.473+7486C>T		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+7486C>T		intron_variant	Intron 3 of 64	5	NM_005045.4	ENSP00000392423.1

Frequencies

GnomAD3 genomes AF: 0.405 AC: 61381 AN: 151622 Hom.: 12672 Cov.: 30

Gnomad AFR AF: 0.345

Gnomad AMI AF: 0.464

Gnomad AMR AF: 0.459

Gnomad ASJ AF: 0.446

Gnomad EAS AF: 0.412

Gnomad SAS AF: 0.472

Gnomad FIN AF: 0.468

Gnomad MID AF: 0.525

Gnomad NFE AF: 0.409

Gnomad OTH AF: 0.453

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

GnomAD4 genome AF: 0.405 AC: 61398 AN: 151742 Hom.: 12664 Cov.: 30 AF XY: 0.410 AC XY: 30416 AN XY: 74132

African (AFR) AF: 0.344 AC: 14235 AN: 41368

American (AMR) AF: 0.458 AC: 6970 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.446 AC: 1545 AN: 3466

East Asian (EAS) AF: 0.411 AC: 2120 AN: 5154

South Asian (SAS) AF: 0.472 AC: 2274 AN: 4814

European-Finnish (FIN) AF: 0.468 AC: 4927 AN: 10518

Middle Eastern (MID) AF: 0.544 AC: 160 AN: 294

European-Non Finnish (NFE) AF: 0.409 AC: 27790 AN: 67888

Other (OTH) AF: 0.453 AC: 954 AN: 2108

Alfa AF: 0.402 Hom.: 17913

Bravo AF: 0.405

Asia WGS AF: 0.446 AC: 1554 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	5.0
DANN	Benign	0.21
PhyloP100		-0.22
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs39347; hg19: chr7-103466498;