NM_005045.4:c.-1_1insGGCGGCGGCGGCGGCGGCGGCGGCGGC

Variant names:

• chr7-103989356-T-TGCCGCCGCCGCCGCCGCCGCCGCCGCC
• rs55656324
• NM_005045.4:c.-1_1insGGCGGCGGCGGCGGCGGCGGCGGCGGC

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_005045.4(RELN):​c.-1_1insGGCGGCGGCGGCGGCGGCGGCGGCGGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000056 (4 hom.)
  • Failed GnomAD Quality Control
• Consequence: RELN NM_005045.4 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.06
• 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: Likely_benign. The variant received -4 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00033 (49/148368) while in subpopulation EAS AF = 0.00298 (14/4698). AF 95% confidence interval is 0.0018. There are 0 homozygotes in GnomAd4. There are 26 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

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.-1_1insGGCGGCGGCGGCGGCGGCGGCGGCGGC		5_prime_UTR	Exon 1 of 65	NP_005036.2
	RELN	NM_173054.3		c.-1_1insGGCGGCGGCGGCGGCGGCGGCGGCGGC		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.-1_1insGGCGGCGGCGGCGGCGGCGGCGGCGGC		5_prime_UTR	Exon 1 of 65	ENSP00000392423.1	P78509-1
	RELN	ENST00000424685.3	TSL:5	c.-1_1insGGCGGCGGCGGCGGCGGCGGCGGCGGC		5_prime_UTR	Exon 1 of 65	ENSP00000388446.3	J3KQ66
	RELN	ENST00000343529.9	TSL:5	c.-1_1insGGCGGCGGCGGCGGCGGCGGCGGCGGC		5_prime_UTR	Exon 1 of 64	ENSP00000345694.5	P78509-2

Frequencies

GnomAD3 genomes AF: 0.000330 AC: 49 AN: 148270 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000298

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000665

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00297

Gnomad SAS AF: 0.000639

Gnomad FIN AF: 0.000696

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000179

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000564 AC: 71 AN: 1259858 Hom.: 4 Cov.: 36 AF XY: 0.0000532 AC XY: 33 AN XY: 620580

African (AFR) AF: 0.000324 AC: 8 AN: 24664

American (AMR) AF: 0.00 AC: 0 AN: 21234

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21048

East Asian (EAS) AF: 0.000221 AC: 6 AN: 27116

South Asian (SAS) AF: 0.000178 AC: 10 AN: 56308

European-Finnish (FIN) AF: 0.0000529 AC: 2 AN: 37800

Middle Eastern (MID) AF: 0.000240 AC: 1 AN: 4160

European-Non Finnish (NFE) AF: 0.0000394 AC: 40 AN: 1015454

Other (OTH) AF: 0.0000768 AC: 4 AN: 52074

GnomAD4 genome AF: 0.000330 AC: 49 AN: 148368 Hom.: 0 Cov.: 0 AF XY: 0.000359 AC XY: 26 AN XY: 72354

African (AFR) AF: 0.000298 AC: 12 AN: 40318

American (AMR) AF: 0.0000665 AC: 1 AN: 15048

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

East Asian (EAS) AF: 0.00298 AC: 14 AN: 4698

South Asian (SAS) AF: 0.000639 AC: 3 AN: 4692

European-Finnish (FIN) AF: 0.000696 AC: 7 AN: 10062

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

European-Non Finnish (NFE) AF: 0.000179 AC: 12 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		2.1

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;