7-103661008-T-G

Variant names:

• chr7-103661008-T-G
• rs727531
• NM_005045.4:c.1441+368A>C

Variant summary

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

The NM_005045.4(RELN):​c.1441+368A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.298 in 152,092 control chromosomes in the GnomAD database, including 6,936 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 0.30 (6936 hom., cov: 32)
• Consequence: RELN NM_005045.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.345
• Publications: 10 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=-0.56).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.364 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RELN	NM_005045.4	c.1441+368A>C		intron_variant	Intron 12 of 64	ENST00000428762.6	NP_005036.2
RELN	NM_173054.3	c.1441+368A>C		intron_variant	Intron 12 of 63		NP_774959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RELN	ENST00000428762.6	c.1441+368A>C		intron_variant	Intron 12 of 64	5	NM_005045.4	ENSP00000392423.1

Frequencies

GnomAD3 genomes AF: 0.298 AC: 45362 AN: 151974 Hom.: 6933 Cov.: 32

Gnomad AFR AF: 0.301

Gnomad AMI AF: 0.345

Gnomad AMR AF: 0.230

Gnomad ASJ AF: 0.338

Gnomad EAS AF: 0.245

Gnomad SAS AF: 0.378

Gnomad FIN AF: 0.267

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.314

Gnomad OTH AF: 0.273

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

GnomAD4 genome AF: 0.298 AC: 45392 AN: 152092 Hom.: 6936 Cov.: 32 AF XY: 0.296 AC XY: 21999 AN XY: 74356

African (AFR) AF: 0.301 AC: 12503 AN: 41496

American (AMR) AF: 0.229 AC: 3498 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.338 AC: 1172 AN: 3470

East Asian (EAS) AF: 0.245 AC: 1265 AN: 5158

South Asian (SAS) AF: 0.378 AC: 1822 AN: 4818

European-Finnish (FIN) AF: 0.267 AC: 2831 AN: 10584

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.314 AC: 21356 AN: 67978

Other (OTH) AF: 0.273 AC: 576 AN: 2110

Alfa AF: 0.305 Hom.: 21261

Bravo AF: 0.295

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	1.6
DANN	Benign	0.81
PhyloP100		0.34
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: rs727531; hg19: chr7-103301455; COSMIC: COSV107407755;