rs362726

Variant names:

• chr7-103566787-T-C
• rs362726
• NM_005045.4:c.4589-28A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005045.4(RELN):​c.4589-28A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.396 in 1,604,664 control chromosomes in the GnomAD database, including 129,804 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (17169 hom., cov: 32)
  • Exomes 𝑓: 0.39 (112635 hom.)
• Consequence: RELN NM_005045.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.256
• Publications: 19 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: Orphanet, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Illumina
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 7-103566787-T-C is Benign according to our data. Variant chr7-103566787-T-C is described in ClinVar as Benign. ClinVar VariationId is 259608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.633 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RELN	NM_005045.4	MANE Select	c.4589-28A>G		intron	N/A	NP_005036.2
	RELN	NM_173054.3		c.4589-28A>G		intron	N/A	NP_774959.1	P78509-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RELN	ENST00000428762.6	TSL:5 MANE Select	c.4589-28A>G		intron	N/A	ENSP00000392423.1	P78509-1
	RELN	ENST00000424685.3	TSL:5	c.4589-28A>G		intron	N/A	ENSP00000388446.3	J3KQ66
	RELN	ENST00000343529.9	TSL:5	c.4589-28A>G		intron	N/A	ENSP00000345694.5	P78509-2

Frequencies

GnomAD3 genomes AF: 0.461 AC: 70106 AN: 151924 Hom.: 17153 Cov.: 32

Gnomad AFR AF: 0.639

Gnomad AMI AF: 0.277

Gnomad AMR AF: 0.457

Gnomad ASJ AF: 0.359

Gnomad EAS AF: 0.474

Gnomad SAS AF: 0.338

Gnomad FIN AF: 0.364

Gnomad MID AF: 0.478

Gnomad NFE AF: 0.384

Gnomad OTH AF: 0.479

GnomAD2 exomes AF: 0.412 AC: 103316 AN: 250738 AF XY: 0.401

Gnomad AFR exome AF: 0.645

Gnomad AMR exome AF: 0.459

Gnomad ASJ exome AF: 0.354

Gnomad EAS exome AF: 0.481

Gnomad FIN exome AF: 0.362

Gnomad NFE exome AF: 0.389

Gnomad OTH exome AF: 0.417

GnomAD4 exome AF: 0.389 AC: 565393 AN: 1452622 Hom.: 112635 Cov.: 30 AF XY: 0.387 AC XY: 279705 AN XY: 723346

African (AFR) AF: 0.652 AC: 21668 AN: 33248

American (AMR) AF: 0.461 AC: 20600 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.350 AC: 9123 AN: 26054

East Asian (EAS) AF: 0.472 AC: 18716 AN: 39624

South Asian (SAS) AF: 0.330 AC: 28389 AN: 86046

European-Finnish (FIN) AF: 0.360 AC: 19220 AN: 53378

Middle Eastern (MID) AF: 0.459 AC: 2632 AN: 5740

European-Non Finnish (NFE) AF: 0.381 AC: 420898 AN: 1103826

Other (OTH) AF: 0.402 AC: 24147 AN: 60008

GnomAD4 genome AF: 0.462 AC: 70169 AN: 152042 Hom.: 17169 Cov.: 32 AF XY: 0.460 AC XY: 34157 AN XY: 74308

African (AFR) AF: 0.639 AC: 26511 AN: 41478

American (AMR) AF: 0.457 AC: 6986 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.359 AC: 1243 AN: 3466

East Asian (EAS) AF: 0.473 AC: 2441 AN: 5162

South Asian (SAS) AF: 0.338 AC: 1628 AN: 4812

European-Finnish (FIN) AF: 0.364 AC: 3842 AN: 10554

Middle Eastern (MID) AF: 0.473 AC: 139 AN: 294

European-Non Finnish (NFE) AF: 0.384 AC: 26115 AN: 67976

Other (OTH) AF: 0.479 AC: 1011 AN: 2110

Alfa AF: 0.406 Hom.: 51915

Bravo AF: 0.482

Asia WGS AF: 0.422 AC: 1468 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Norman-Roberts syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	11
DANN	Benign	0.63
PhyloP100		-0.26
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs362726; hg19: chr7-103207234; COSMIC: COSV59024661;