NM_005045.4:c.5195_5208dupTTCCACTCTCCACC

Variant names:

• chr7-103565279-T-TGGTGGAGAGTGGAA
• rs587780436
• NM_005045.4:c.5195_5208dupTTCCACTCTCCACC

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_005045.4(RELN):​c.5195_5208dupTTCCACTCTCCACC​(p.Ile1737PhefsTer97) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RELN NM_005045.4 frameshift, splice_region
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.27
• Publications: 0 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 7-103565279-T-TGGTGGAGAGTGGAA is Pathogenic according to our data. Variant chr7-103565279-T-TGGTGGAGAGTGGAA is described in CliVar as Pathogenic. Clinvar id is 130111.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-103565279-T-TGGTGGAGAGTGGAA is described in CliVar as Pathogenic. Clinvar id is 130111.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-103565279-T-TGGTGGAGAGTGGAA is described in CliVar as Pathogenic. Clinvar id is 130111.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-103565279-T-TGGTGGAGAGTGGAA is described in CliVar as Pathogenic. Clinvar id is 130111.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-103565279-T-TGGTGGAGAGTGGAA is described in CliVar as Pathogenic. Clinvar id is 130111.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RELN	NM_005045.4	c.5195_5208dupTTCCACTCTCCACC	p.Ile1737PhefsTer97	frameshift_variant, splice_region_variant	Exon 34 of 65	ENST00000428762.6	NP_005036.2
RELN	NM_173054.3	c.5195_5208dupTTCCACTCTCCACC	p.Ile1737PhefsTer97	frameshift_variant, splice_region_variant	Exon 34 of 64		NP_774959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RELN	ENST00000428762.6	c.5195_5208dupTTCCACTCTCCACC	p.Ile1737PhefsTer97	frameshift_variant, splice_region_variant	Exon 34 of 65	5	NM_005045.4	ENSP00000392423.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Norman-Roberts syndrome Pathogenic:1

Jun 12, 2013

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs587780436; hg19: chr7-103205726;