7-103905961-A-G

Variant names:

• chr7-103905961-A-G
• rs802786
• NM_005045.4:c.337+11114T>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.337+11114T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.828 in 152,024 control chromosomes in the GnomAD database, including 52,695 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 0.83 (52695 hom., cov: 30)
• Consequence: RELN NM_005045.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.05
• 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=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.952 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RELN	NM_005045.4	c.337+11114T>C		intron_variant	Intron 2 of 64	ENST00000428762.6	NP_005036.2
RELN	NM_173054.3	c.337+11114T>C		intron_variant	Intron 2 of 63		NP_774959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RELN	ENST00000428762.6	c.337+11114T>C		intron_variant	Intron 2 of 64	5	NM_005045.4	ENSP00000392423.1

Frequencies

GnomAD3 genomes AF: 0.828 AC: 125819 AN: 151906 Hom.: 52633 Cov.: 30

Gnomad AFR AF: 0.960

Gnomad AMI AF: 0.810

Gnomad AMR AF: 0.769

Gnomad ASJ AF: 0.664

Gnomad EAS AF: 0.780

Gnomad SAS AF: 0.820

Gnomad FIN AF: 0.768

Gnomad MID AF: 0.652

Gnomad NFE AF: 0.786

Gnomad OTH AF: 0.773

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

GnomAD4 genome AF: 0.828 AC: 125946 AN: 152024 Hom.: 52695 Cov.: 30 AF XY: 0.825 AC XY: 61257 AN XY: 74278

African (AFR) AF: 0.960 AC: 39843 AN: 41516

American (AMR) AF: 0.770 AC: 11728 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.664 AC: 2306 AN: 3472

East Asian (EAS) AF: 0.781 AC: 4026 AN: 5154

South Asian (SAS) AF: 0.820 AC: 3944 AN: 4808

European-Finnish (FIN) AF: 0.768 AC: 8107 AN: 10558

Middle Eastern (MID) AF: 0.656 AC: 193 AN: 294

European-Non Finnish (NFE) AF: 0.786 AC: 53427 AN: 67960

Other (OTH) AF: 0.773 AC: 1633 AN: 2112

Alfa AF: 0.792 Hom.: 209471

Bravo AF: 0.829

Asia WGS AF: 0.832 AC: 2895 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.26
DANN	Benign	0.25
PhyloP100		-1.1
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: rs802786; hg19: chr7-103546408;