7-103726145-A-G

Variant names:

• chr7-103726145-A-G
• rs563264
• NM_005045.4:c.753+1966T>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.753+1966T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.118 in 152,236 control chromosomes in the GnomAD database, including 1,164 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 0.12 (1164 hom., cov: 32)
• Consequence: RELN NM_005045.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.30
• Publications: 3 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=-0.8).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.129 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.753+1966T>C		intron	N/A	NP_005036.2
	RELN	NM_173054.3		c.753+1966T>C		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.753+1966T>C		intron	N/A	ENSP00000392423.1
	RELN	ENST00000424685.3	TSL:5	c.753+1966T>C		intron	N/A	ENSP00000388446.3
	RELN	ENST00000343529.9	TSL:5	c.753+1966T>C		intron	N/A	ENSP00000345694.5

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17938 AN: 152118 Hom.: 1162 Cov.: 32

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.0855

Gnomad AMR AF: 0.0997

Gnomad ASJ AF: 0.126

Gnomad EAS AF: 0.0269

Gnomad SAS AF: 0.0712

Gnomad FIN AF: 0.110

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.131

Gnomad OTH AF: 0.145

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

GnomAD4 genome AF: 0.118 AC: 17948 AN: 152236 Hom.: 1164 Cov.: 32 AF XY: 0.117 AC XY: 8729 AN XY: 74426

African (AFR) AF: 0.119 AC: 4944 AN: 41540

American (AMR) AF: 0.0994 AC: 1520 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 435 AN: 3466

East Asian (EAS) AF: 0.0268 AC: 139 AN: 5190

South Asian (SAS) AF: 0.0721 AC: 348 AN: 4826

European-Finnish (FIN) AF: 0.110 AC: 1167 AN: 10598

Middle Eastern (MID) AF: 0.276 AC: 81 AN: 294

European-Non Finnish (NFE) AF: 0.131 AC: 8932 AN: 68004

Other (OTH) AF: 0.144 AC: 304 AN: 2116

Alfa AF: 0.128 Hom.: 726

Bravo AF: 0.119

Asia WGS AF: 0.0550 AC: 192 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.0
DANN	Benign	0.58
PhyloP100		1.3
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: rs563264; hg19: chr7-103366592;