7-103989356-TGCCGCCGCCGCCGCC-TGCCGCC

Variant names:

• chr7-103989356-TGCCGCCGCC-T
• rs55656324
• NM_005045.4:c.-9_-1delGGCGGCGGC

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_005045.4(RELN):​c.-9_-1delGGCGGCGGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000224 in 1,408,184 control chromosomes in the GnomAD database, including 17 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00023 (17 hom.)
• Consequence: RELN NM_005045.4 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.13
• 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: Orphanet, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Illumina
• 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 -8 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000175 (26/148368) while in subpopulation EAS AF = 0.00106 (5/4698). AF 95% confidence interval is 0.000419. There are 0 homozygotes in GnomAd4. There are 13 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 17 AR,AD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RELN	NM_005045.4	MANE Select	c.-9_-1delGGCGGCGGC		5_prime_UTR	Exon 1 of 65	NP_005036.2
	RELN	NM_173054.3		c.-9_-1delGGCGGCGGC		5_prime_UTR	Exon 1 of 64	NP_774959.1	P78509-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RELN	ENST00000428762.6	TSL:5 MANE Select	c.-9_-1delGGCGGCGGC		5_prime_UTR	Exon 1 of 65	ENSP00000392423.1	P78509-1
	RELN	ENST00000424685.3	TSL:5	c.-9_-1delGGCGGCGGC		5_prime_UTR	Exon 1 of 65	ENSP00000388446.3	J3KQ66
	RELN	ENST00000343529.9	TSL:5	c.-9_-1delGGCGGCGGC		5_prime_UTR	Exon 1 of 64	ENSP00000345694.5	P78509-2

Frequencies

GnomAD3 genomes AF: 0.000175 AC: 26 AN: 148270 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000995

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000133

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00106

Gnomad SAS AF: 0.000426

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000194

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000229 AC: 289 AN: 1259816 Hom.: 17 AF XY: 0.000242 AC XY: 150 AN XY: 620560

African (AFR) AF: 0.000122 AC: 3 AN: 24664

American (AMR) AF: 0.000801 AC: 17 AN: 21228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21046

East Asian (EAS) AF: 0.00159 AC: 43 AN: 27114

South Asian (SAS) AF: 0.000995 AC: 56 AN: 56300

European-Finnish (FIN) AF: 0.0000265 AC: 1 AN: 37796

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4160

European-Non Finnish (NFE) AF: 0.000147 AC: 149 AN: 1015434

Other (OTH) AF: 0.000384 AC: 20 AN: 52074

GnomAD4 genome AF: 0.000175 AC: 26 AN: 148368 Hom.: 0 Cov.: 0 AF XY: 0.000180 AC XY: 13 AN XY: 72354

African (AFR) AF: 0.0000992 AC: 4 AN: 40318

American (AMR) AF: 0.000133 AC: 2 AN: 15048

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3446

East Asian (EAS) AF: 0.00106 AC: 5 AN: 4698

South Asian (SAS) AF: 0.000426 AC: 2 AN: 4692

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10062

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 278

European-Non Finnish (NFE) AF: 0.000194 AC: 13 AN: 66874

Other (OTH) AF: 0.00 AC: 0 AN: 2060

Alfa AF: 0.00 Hom.: 609

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.1

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs55656324; hg19: chr7-103629803;