chr7-103989356-T-TGCCGCCGCCGCCGCC

Variant names:

• chr7-103989356-T-TGCCGCCGCCGCCGCC
• rs55656324
• NM_005045.4:c.-15_-1dupGGCGGCGGCGGCGGC

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The NM_005045.4(RELN):​c.-15_-1dupGGCGGCGGCGGCGGC 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.035 (151 hom., cov: 0)
  • Exomes 𝑓: 0.023 (709 hom.)
  • Failed GnomAD Quality Control
• Consequence: RELN NM_005045.4 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• 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-T-TGCCGCCGCCGCCGCC is Benign according to our data. Variant chr7-103989356-T-TGCCGCCGCCGCCGCC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 358425.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.115 is higher than 0.05.

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.-15_-1dupGGCGGCGGCGGCGGC		5_prime_UTR	Exon 1 of 65	NP_005036.2
	RELN	NM_173054.3		c.-15_-1dupGGCGGCGGCGGCGGC		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.-15_-1dupGGCGGCGGCGGCGGC		5_prime_UTR	Exon 1 of 65	ENSP00000392423.1	P78509-1
	RELN	ENST00000424685.3	TSL:5	c.-15_-1dupGGCGGCGGCGGCGGC		5_prime_UTR	Exon 1 of 65	ENSP00000388446.3	J3KQ66
	RELN	ENST00000343529.9	TSL:5	c.-15_-1dupGGCGGCGGCGGCGGC		5_prime_UTR	Exon 1 of 64	ENSP00000345694.5	P78509-2

Frequencies

GnomAD3 genomes AF: 0.0351 AC: 5197 AN: 148234 Hom.: 152 Cov.: 0

Gnomad AFR AF: 0.0238

Gnomad AMI AF: 0.0280

Gnomad AMR AF: 0.0449

Gnomad ASJ AF: 0.0258

Gnomad EAS AF: 0.0914

Gnomad SAS AF: 0.123

Gnomad FIN AF: 0.0272

Gnomad MID AF: 0.0405

Gnomad NFE AF: 0.0309

Gnomad OTH AF: 0.0447

GnomAD2 exomes AF: 0.00211 AC: 135 AN: 63892 AF XY: 0.00222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000266

Gnomad ASJ exome AF: 0.000499

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00475

Gnomad NFE exome AF: 0.00239

Gnomad OTH exome AF: 0.00179

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0232 AC: 29132 AN: 1254916 Hom.: 709 Cov.: 36 AF XY: 0.0227 AC XY: 14062 AN XY: 618120

African (AFR) AF: 0.0172 AC: 422 AN: 24592

American (AMR) AF: 0.0179 AC: 377 AN: 21088

Ashkenazi Jewish (ASJ) AF: 0.0128 AC: 268 AN: 20946

East Asian (EAS) AF: 0.0537 AC: 1401 AN: 26100

South Asian (SAS) AF: 0.0361 AC: 2023 AN: 56016

European-Finnish (FIN) AF: 0.0166 AC: 623 AN: 37504

Middle Eastern (MID) AF: 0.0282 AC: 116 AN: 4120

European-Non Finnish (NFE) AF: 0.0223 AC: 22535 AN: 1012782

Other (OTH) AF: 0.0264 AC: 1367 AN: 51768

GnomAD4 genome AF: 0.0350 AC: 5195 AN: 148332 Hom.: 151 Cov.: 0 AF XY: 0.0359 AC XY: 2597 AN XY: 72342

African (AFR) AF: 0.0238 AC: 958 AN: 40308

American (AMR) AF: 0.0447 AC: 672 AN: 15046

Ashkenazi Jewish (ASJ) AF: 0.0258 AC: 89 AN: 3446

East Asian (EAS) AF: 0.0922 AC: 433 AN: 4698

South Asian (SAS) AF: 0.123 AC: 577 AN: 4690

European-Finnish (FIN) AF: 0.0272 AC: 273 AN: 10054

Middle Eastern (MID) AF: 0.0396 AC: 11 AN: 278

European-Non Finnish (NFE) AF: 0.0309 AC: 2066 AN: 66862

Other (OTH) AF: 0.0442 AC: 91 AN: 2058

Alfa AF: 0.0150 Hom.: 609

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	1	-	Lissencephaly, Recessive (1)
-	-	1	not provided (1)
-	-	1	RELN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.1
Mutation Taster		=100/0	polymorphism (auto)

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;