NM_005045.4:c.474-9041T>A

Variant names:

• chr7-103785668-A-T
• rs262355
• NM_005045.4:c.474-9041T>A

Variant summary

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

The NM_005045.4(RELN):​c.474-9041T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.672 in 151,928 control chromosomes in the GnomAD database, including 34,555 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 0.67 (34555 hom., cov: 32)
• Consequence: RELN NM_005045.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.739
• Publications: 12 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=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.722 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RELN	NM_005045.4	c.474-9041T>A		intron_variant	Intron 3 of 64	ENST00000428762.6	NP_005036.2
RELN	NM_173054.3	c.474-9041T>A		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.474-9041T>A		intron_variant	Intron 3 of 64	5	NM_005045.4	ENSP00000392423.1

Frequencies

GnomAD3 genomes AF: 0.672 AC: 102013 AN: 151810 Hom.: 34542 Cov.: 32

Gnomad AFR AF: 0.726

Gnomad AMI AF: 0.552

Gnomad AMR AF: 0.696

Gnomad ASJ AF: 0.653

Gnomad EAS AF: 0.742

Gnomad SAS AF: 0.740

Gnomad FIN AF: 0.589

Gnomad MID AF: 0.747

Gnomad NFE AF: 0.638

Gnomad OTH AF: 0.694

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

GnomAD4 genome AF: 0.672 AC: 102075 AN: 151928 Hom.: 34555 Cov.: 32 AF XY: 0.672 AC XY: 49903 AN XY: 74252

African (AFR) AF: 0.725 AC: 30093 AN: 41484

American (AMR) AF: 0.697 AC: 10618 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.653 AC: 2268 AN: 3472

East Asian (EAS) AF: 0.742 AC: 3835 AN: 5168

South Asian (SAS) AF: 0.741 AC: 3573 AN: 4824

European-Finnish (FIN) AF: 0.589 AC: 6202 AN: 10536

Middle Eastern (MID) AF: 0.745 AC: 219 AN: 294

European-Non Finnish (NFE) AF: 0.638 AC: 43313 AN: 67892

Other (OTH) AF: 0.690 AC: 1453 AN: 2106

Alfa AF: 0.658 Hom.: 4110

Bravo AF: 0.686

Asia WGS AF: 0.714 AC: 2484 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.7
DANN	Benign	0.77
PhyloP100		0.74
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: rs262355; hg19: chr7-103426115;