7-103630182-GAA-GAAAA

Variant names:

• chr7-103630182-G-GAA
• rs571882672
• NM_005045.4:c.2466-8_2466-7dupTT

Variant summary

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

The NM_005045.4(RELN):​c.2466-8_2466-7dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000164 in 1,121,514 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: 𝑓 0.0 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RELN NM_005045.4 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.884
• Publications: 1 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 0 ACMG points.

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.2466-8_2466-7dupTT		splice_region intron	N/A	NP_005036.2
	RELN	NM_173054.3		c.2466-8_2466-7dupTT		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_2466-6insTT		splice_region intron	N/A	ENSP00000392423.1	P78509-1
	RELN	ENST00000424685.3	TSL:5	c.2466-7_2466-6insTT		splice_region intron	N/A	ENSP00000388446.3	J3KQ66
	RELN	ENST00000343529.9	TSL:5	c.2466-7_2466-6insTT		splice_region intron	N/A	ENSP00000345694.5	P78509-2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 138614 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000424 AC: 43 AN: 101368 AF XY: 0.000550

Gnomad AFR exome AF: 0.000277

Gnomad AMR exome AF: 0.000250

Gnomad ASJ exome AF: 0.000283

Gnomad EAS exome AF: 0.000131

Gnomad FIN exome AF: 0.000435

Gnomad NFE exome AF: 0.000446

Gnomad OTH exome AF: 0.000441

GnomAD4 exome AF: 0.000164 AC: 184 AN: 1121514 Hom.: 0 Cov.: 23 AF XY: 0.000161 AC XY: 90 AN XY: 558698

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

African (AFR) AF: 0.000239 AC: 6 AN: 25106

American (AMR) AF: 0.000191 AC: 6 AN: 31490

Ashkenazi Jewish (ASJ) AF: 0.000210 AC: 4 AN: 19088

East Asian (EAS) AF: 0.0000677 AC: 2 AN: 29550

South Asian (SAS) AF: 0.000264 AC: 17 AN: 64426

European-Finnish (FIN) AF: 0.0000514 AC: 2 AN: 38902

Middle Eastern (MID) AF: 0.000438 AC: 2 AN: 4566

European-Non Finnish (NFE) AF: 0.000159 AC: 137 AN: 862474

Other (OTH) AF: 0.000174 AC: 8 AN: 45912

⚠️ 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 Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 138614 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 67026

African (AFR) AF: 0.00 AC: 0 AN: 37668

American (AMR) AF: 0.00 AC: 0 AN: 13892

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3298

East Asian (EAS) AF: 0.00 AC: 0 AN: 4778

South Asian (SAS) AF: 0.00 AC: 0 AN: 4442

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7982

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 63538

Other (OTH) AF: 0.00 AC: 0 AN: 1860

Alfa AF: 0.000988 Hom.: 0

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;