7-103989356-TGCCGCCGCCGCCGCC-TGCCGCCGCCGCC

Variant names:

• chr7-103989356-TGCC-T
• rs55656324
• NM_005045.4:c.-3_-1delGGC

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_005045.4(RELN):​c.-3_-1delGGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00167 in 1,396,900 control chromosomes in the GnomAD database, including 35 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 0)
  • Exomes 𝑓: 0.0017 (34 hom.)
• Consequence: RELN NM_005045.4 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• 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: Benign. The variant received -9 ACMG points.

• BP6: Variant 7-103989356-TGCC-T is Benign according to our data. Variant chr7-103989356-TGCC-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 358429.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00159 (236/148362) while in subpopulation EAS AF = 0.00404 (19/4698). AF 95% confidence interval is 0.00265. There are 1 homozygotes in GnomAd4. There are 120 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 34 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.-3_-1delGGC		5_prime_UTR	Exon 1 of 65	NP_005036.2
	RELN	NM_173054.3		c.-3_-1delGGC		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.-3_-1delGGC		5_prime_UTR	Exon 1 of 65	ENSP00000392423.1	P78509-1
	RELN	ENST00000424685.3	TSL:5	c.-3_-1delGGC		5_prime_UTR	Exon 1 of 65	ENSP00000388446.3	J3KQ66
	RELN	ENST00000343529.9	TSL:5	c.-3_-1delGGC		5_prime_UTR	Exon 1 of 64	ENSP00000345694.5	P78509-2

Frequencies

GnomAD3 genomes AF: 0.00158 AC: 234 AN: 148264 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.00308

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00220

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00403

Gnomad SAS AF: 0.00149

Gnomad FIN AF: 0.000298

Gnomad MID AF: 0.00676

Gnomad NFE AF: 0.000643

Gnomad OTH AF: 0.00147

GnomAD2 exomes AF: 0.0113 AC: 720 AN: 63892 AF XY: 0.00989

Gnomad AFR exome AF: 0.0245

Gnomad AMR exome AF: 0.0187

Gnomad ASJ exome AF: 0.0115

Gnomad EAS exome AF: 0.0303

Gnomad FIN exome AF: 0.00695

Gnomad NFE exome AF: 0.00926

Gnomad OTH exome AF: 0.0149

GnomAD4 exome AF: 0.00168 AC: 2097 AN: 1248538 Hom.: 34 AF XY: 0.00170 AC XY: 1043 AN XY: 614850

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

African (AFR) AF: 0.00466 AC: 114 AN: 24482

American (AMR) AF: 0.00711 AC: 146 AN: 20548

Ashkenazi Jewish (ASJ) AF: 0.00338 AC: 70 AN: 20688

East Asian (EAS) AF: 0.00296 AC: 80 AN: 27014

South Asian (SAS) AF: 0.00267 AC: 148 AN: 55498

European-Finnish (FIN) AF: 0.00132 AC: 49 AN: 37208

Middle Eastern (MID) AF: 0.00145 AC: 6 AN: 4126

European-Non Finnish (NFE) AF: 0.00134 AC: 1352 AN: 1007430

Other (OTH) AF: 0.00256 AC: 132 AN: 51544

⚠️ 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 AF: 0.00159 AC: 236 AN: 148362 Hom.: 1 Cov.: 0 AF XY: 0.00166 AC XY: 120 AN XY: 72350

African (AFR) AF: 0.00308 AC: 124 AN: 40316

American (AMR) AF: 0.00219 AC: 33 AN: 15048

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

East Asian (EAS) AF: 0.00404 AC: 19 AN: 4698

South Asian (SAS) AF: 0.00128 AC: 6 AN: 4692

European-Finnish (FIN) AF: 0.000298 AC: 3 AN: 10060

Middle Eastern (MID) AF: 0.00360 AC: 1 AN: 278

European-Non Finnish (NFE) AF: 0.000643 AC: 43 AN: 66872

Other (OTH) AF: 0.00340 AC: 7 AN: 2060

Alfa AF: 0.00 Hom.: 609

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	-	Lissencephaly, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.1
Mutation Taster		=299/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs55656324; hg19: chr7-103629803;