NM_005045.4:c.1144-5795T>A

Variant names:

• chr7-103688056-A-T
• rs12705141
• NM_005045.4:c.1144-5795T>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_005045.4(RELN):​c.1144-5795T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.228 in 151,980 control chromosomes in the GnomAD database, including 3,975 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 0.23 (3975 hom., cov: 32)
• Consequence: RELN NM_005045.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.37
• Publications: 2 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.244 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.1144-5795T>A		intron	N/A	NP_005036.2
	RELN	NM_173054.3		c.1144-5795T>A		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.1144-5795T>A		intron	N/A	ENSP00000392423.1
	RELN	ENST00000424685.3	TSL:5	c.1144-5795T>A		intron	N/A	ENSP00000388446.3
	RELN	ENST00000343529.9	TSL:5	c.1144-5795T>A		intron	N/A	ENSP00000345694.5

Frequencies

GnomAD3 genomes AF: 0.228 AC: 34581 AN: 151862 Hom.: 3972 Cov.: 32

Gnomad AFR AF: 0.197

Gnomad AMI AF: 0.235

Gnomad AMR AF: 0.226

Gnomad ASJ AF: 0.271

Gnomad EAS AF: 0.164

Gnomad SAS AF: 0.240

Gnomad FIN AF: 0.223

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.247

Gnomad OTH AF: 0.260

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

GnomAD4 genome AF: 0.228 AC: 34589 AN: 151980 Hom.: 3975 Cov.: 32 AF XY: 0.229 AC XY: 16977 AN XY: 74282

African (AFR) AF: 0.197 AC: 8174 AN: 41458

American (AMR) AF: 0.226 AC: 3435 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.271 AC: 941 AN: 3472

East Asian (EAS) AF: 0.163 AC: 842 AN: 5162

South Asian (SAS) AF: 0.241 AC: 1162 AN: 4822

European-Finnish (FIN) AF: 0.223 AC: 2355 AN: 10570

Middle Eastern (MID) AF: 0.391 AC: 115 AN: 294

European-Non Finnish (NFE) AF: 0.247 AC: 16803 AN: 67946

Other (OTH) AF: 0.259 AC: 548 AN: 2114

Alfa AF: 0.222 Hom.: 482

Bravo AF: 0.226

Asia WGS AF: 0.219 AC: 764 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	12
DANN	Benign	0.76
PhyloP100		1.4
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: rs12705141; hg19: chr7-103328503;