chr7-103836220-A-G

Variant names:

• chr7-103836220-A-G
• rs39374
• NM_005045.4:c.338-2548T>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.338-2548T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.366 in 152,000 control chromosomes in the GnomAD database, including 10,664 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 0.37 (10664 hom., cov: 32)
• Consequence: RELN NM_005045.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0580
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.421 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.338-2548T>C		intron	N/A	NP_005036.2
	RELN	NM_173054.3		c.338-2548T>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.338-2548T>C		intron	N/A	ENSP00000392423.1
	RELN	ENST00000424685.3	TSL:5	c.338-2548T>C		intron	N/A	ENSP00000388446.3
	RELN	ENST00000343529.9	TSL:5	c.338-2548T>C		intron	N/A	ENSP00000345694.5

Frequencies

GnomAD3 genomes AF: 0.366 AC: 55638 AN: 151882 Hom.: 10662 Cov.: 32

Gnomad AFR AF: 0.333

Gnomad AMI AF: 0.376

Gnomad AMR AF: 0.344

Gnomad ASJ AF: 0.369

Gnomad EAS AF: 0.154

Gnomad SAS AF: 0.189

Gnomad FIN AF: 0.338

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.425

Gnomad OTH AF: 0.343

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

GnomAD4 genome AF: 0.366 AC: 55651 AN: 152000 Hom.: 10664 Cov.: 32 AF XY: 0.359 AC XY: 26636 AN XY: 74294

African (AFR) AF: 0.333 AC: 13786 AN: 41398

American (AMR) AF: 0.344 AC: 5261 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.369 AC: 1281 AN: 3470

East Asian (EAS) AF: 0.154 AC: 798 AN: 5176

South Asian (SAS) AF: 0.190 AC: 918 AN: 4820

European-Finnish (FIN) AF: 0.338 AC: 3571 AN: 10558

Middle Eastern (MID) AF: 0.262 AC: 77 AN: 294

European-Non Finnish (NFE) AF: 0.425 AC: 28894 AN: 67974

Other (OTH) AF: 0.342 AC: 722 AN: 2114

Alfa AF: 0.399 Hom.: 1532

Bravo AF: 0.363

Asia WGS AF: 0.194 AC: 675 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.4
DANN	Benign	0.49
PhyloP100		0.058
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: rs39374; hg19: chr7-103476667;