rs499953

Variant names:

• chr7-103757219-G-T
• rs499953
• NM_005045.4:c.545-4005C>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.545-4005C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.542 in 151,910 control chromosomes in the GnomAD database, including 24,039 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 0.54 (24039 hom., cov: 32)
• Consequence: RELN NM_005045.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.173
• Publications: 2 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=-0.78).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.664 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005045.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RELN	NM_005045.4	MANE Select	c.545-4005C>A		intron	N/A	NP_005036.2
	RELN	NM_173054.3		c.545-4005C>A		intron	N/A	NP_774959.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RELN	ENST00000428762.6	TSL:5 MANE Select	c.545-4005C>A		intron	N/A	ENSP00000392423.1
	RELN	ENST00000424685.3	TSL:5	c.545-4005C>A		intron	N/A	ENSP00000388446.3
	RELN	ENST00000343529.9	TSL:5	c.545-4005C>A		intron	N/A	ENSP00000345694.5

Frequencies

GnomAD3 genomes AF: 0.542 AC: 82334 AN: 151794 Hom.: 24043 Cov.: 32

Gnomad AFR AF: 0.330

Gnomad AMI AF: 0.765

Gnomad AMR AF: 0.542

Gnomad ASJ AF: 0.618

Gnomad EAS AF: 0.405

Gnomad SAS AF: 0.450

Gnomad FIN AF: 0.610

Gnomad MID AF: 0.671

Gnomad NFE AF: 0.669

Gnomad OTH AF: 0.595

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

GnomAD4 genome AF: 0.542 AC: 82331 AN: 151910 Hom.: 24039 Cov.: 32 AF XY: 0.537 AC XY: 39893 AN XY: 74264

African (AFR) AF: 0.330 AC: 13641 AN: 41382

American (AMR) AF: 0.541 AC: 8260 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.618 AC: 2144 AN: 3468

East Asian (EAS) AF: 0.406 AC: 2094 AN: 5162

South Asian (SAS) AF: 0.453 AC: 2179 AN: 4812

European-Finnish (FIN) AF: 0.610 AC: 6436 AN: 10552

Middle Eastern (MID) AF: 0.673 AC: 198 AN: 294

European-Non Finnish (NFE) AF: 0.669 AC: 45446 AN: 67954

Other (OTH) AF: 0.588 AC: 1237 AN: 2102

Alfa AF: 0.624 Hom.: 55988

Bravo AF: 0.529

Asia WGS AF: 0.408 AC: 1419 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	4.9
DANN	Benign	0.70
PhyloP100		0.17
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: rs499953; hg19: chr7-103397666;