7-103630182-GAA-GAAAAA

Variant names:

• chr7-103630182-G-GAAA
• rs571882672
• NM_005045.4:c.2466-9_2466-7dupTTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005045.4(RELN):​c.2466-9_2466-7dupTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000445 in 1,124,210 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000044 (0 hom.)
• Consequence: RELN NM_005045.4 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.884
• 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: Orphanet, Illumina, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.2466-9_2466-7dupTTT		splice_region intron	N/A	NP_005036.2
	RELN	NM_173054.3		c.2466-9_2466-7dupTTT		splice_region intron	N/A	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.2466-7_2466-6insTTT		splice_region intron	N/A	ENSP00000392423.1	P78509-1
	RELN	ENST00000424685.3	TSL:5	c.2466-7_2466-6insTTT		splice_region intron	N/A	ENSP00000388446.3	J3KQ66
	RELN	ENST00000343529.9	TSL:5	c.2466-7_2466-6insTTT		splice_region intron	N/A	ENSP00000345694.5	P78509-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000445 AC: 5 AN: 1124210 Hom.: 0 Cov.: 23 AF XY: 0.00000357 AC XY: 2 AN XY: 559978

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25182

American (AMR) AF: 0.00 AC: 0 AN: 31542

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19110

East Asian (EAS) AF: 0.00 AC: 0 AN: 29606

South Asian (SAS) AF: 0.00 AC: 0 AN: 64542

European-Finnish (FIN) AF: 0.0000257 AC: 1 AN: 38976

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4572

European-Non Finnish (NFE) AF: 0.00000463 AC: 4 AN: 864698

Other (OTH) AF: 0.00 AC: 0 AN: 45982

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.88

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs571882672;

hg19: chr7-103270629;