7-103978821-T-C

Variant names:

• chr7-103978821-T-C
• rs4636135
• NM_005045.4:c.226+10310A>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.226+10310A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.701 in 152,042 control chromosomes in the GnomAD database, including 37,947 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 0.70 (37947 hom., cov: 32)
• Consequence: RELN NM_005045.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.11
• Publications: 1 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=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.814 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RELN	NM_005045.4	c.226+10310A>G		intron_variant	Intron 1 of 64	ENST00000428762.6	NP_005036.2
RELN	NM_173054.3	c.226+10310A>G		intron_variant	Intron 1 of 63		NP_774959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RELN	ENST00000428762.6	c.226+10310A>G		intron_variant	Intron 1 of 64	5	NM_005045.4	ENSP00000392423.1

Frequencies

GnomAD3 genomes AF: 0.701 AC: 106535 AN: 151924 Hom.: 37896 Cov.: 32

Gnomad AFR AF: 0.821

Gnomad AMI AF: 0.675

Gnomad AMR AF: 0.604

Gnomad ASJ AF: 0.745

Gnomad EAS AF: 0.642

Gnomad SAS AF: 0.617

Gnomad FIN AF: 0.648

Gnomad MID AF: 0.803

Gnomad NFE AF: 0.666

Gnomad OTH AF: 0.737

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

GnomAD4 genome AF: 0.701 AC: 106641 AN: 152042 Hom.: 37947 Cov.: 32 AF XY: 0.696 AC XY: 51717 AN XY: 74284

African (AFR) AF: 0.821 AC: 34065 AN: 41498

American (AMR) AF: 0.603 AC: 9215 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.745 AC: 2584 AN: 3470

East Asian (EAS) AF: 0.642 AC: 3318 AN: 5172

South Asian (SAS) AF: 0.618 AC: 2978 AN: 4816

European-Finnish (FIN) AF: 0.648 AC: 6834 AN: 10544

Middle Eastern (MID) AF: 0.805 AC: 235 AN: 292

European-Non Finnish (NFE) AF: 0.666 AC: 45236 AN: 67954

Other (OTH) AF: 0.740 AC: 1562 AN: 2112

Alfa AF: 0.677 Hom.: 4329

Bravo AF: 0.707

Asia WGS AF: 0.627 AC: 2182 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	7.2
DANN	Benign	0.62
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: rs4636135; hg19: chr7-103619268;