chr7-103581859-T-C

Variant names:

• chr7-103581859-T-C
• rs2237628
• NM_005045.4:c.4146-6154A>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.4146-6154A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.472 in 151,458 control chromosomes in the GnomAD database, including 16,908 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 0.47 (16908 hom., cov: 29)
• Consequence: RELN NM_005045.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0180
• Publications: 5 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=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.504 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.4146-6154A>G		intron	N/A	NP_005036.2
	RELN	NM_173054.3		c.4146-6154A>G		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.4146-6154A>G		intron	N/A	ENSP00000392423.1
	RELN	ENST00000424685.3	TSL:5	c.4146-6154A>G		intron	N/A	ENSP00000388446.3
	RELN	ENST00000343529.9	TSL:5	c.4146-6154A>G		intron	N/A	ENSP00000345694.5

Frequencies

GnomAD3 genomes AF: 0.472 AC: 71415 AN: 151340 Hom.: 16900 Cov.: 29

Gnomad AFR AF: 0.439

Gnomad AMI AF: 0.491

Gnomad AMR AF: 0.445

Gnomad ASJ AF: 0.487

Gnomad EAS AF: 0.505

Gnomad SAS AF: 0.521

Gnomad FIN AF: 0.461

Gnomad MID AF: 0.382

Gnomad NFE AF: 0.494

Gnomad OTH AF: 0.453

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

GnomAD4 genome AF: 0.472 AC: 71435 AN: 151458 Hom.: 16908 Cov.: 29 AF XY: 0.471 AC XY: 34857 AN XY: 73972

African (AFR) AF: 0.438 AC: 18056 AN: 41244

American (AMR) AF: 0.444 AC: 6751 AN: 15188

Ashkenazi Jewish (ASJ) AF: 0.487 AC: 1685 AN: 3462

East Asian (EAS) AF: 0.505 AC: 2593 AN: 5134

South Asian (SAS) AF: 0.521 AC: 2497 AN: 4790

European-Finnish (FIN) AF: 0.461 AC: 4816 AN: 10458

Middle Eastern (MID) AF: 0.373 AC: 109 AN: 292

European-Non Finnish (NFE) AF: 0.494 AC: 33525 AN: 67874

Other (OTH) AF: 0.454 AC: 955 AN: 2104

Alfa AF: 0.488 Hom.: 69478

Bravo AF: 0.471

Asia WGS AF: 0.478 AC: 1667 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.1
DANN	Benign	0.41
PhyloP100		-0.018
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: rs2237628; hg19: chr7-103222306; COSMIC: COSV107407750;