7-103565554-GAA-GAAA

Position:

• chr7-103565554-GAA-GAAA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_005045.4(RELN):​c.4937-4_4937-3insT variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (5830 hom., cov: 0)
  • Exomes 𝑓: 0.30 (9657 hom.)
  • Failed GnomAD Quality Control
• Consequence: RELN NM_005045.4 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.186

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 7-103565554-G-GA is Benign according to our data. Variant chr7-103565554-G-GA is described in ClinVar as [Benign]. Clinvar id is 358398.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.299 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RELN	NM_005045.4	c.4937-4_4937-3insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000428762.6	NP_005036.2
RELN	NM_173054.3	c.4937-4_4937-3insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_774959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RELN	ENST00000428762.6	c.4937-4_4937-3insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_005045.4	ENSP00000392423	P5

Frequencies

GnomAD3 genomes AF: 0.280 AC: 41368 AN: 147874 Hom.: 5827 Cov.: 0

Gnomad AFR AF: 0.286

Gnomad AMI AF: 0.174

Gnomad AMR AF: 0.236

Gnomad ASJ AF: 0.277

Gnomad EAS AF: 0.0792

Gnomad SAS AF: 0.267

Gnomad FIN AF: 0.279

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.302

Gnomad OTH AF: 0.315

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.304 AC: 352640 AN: 1160146 Hom.: 9657 Cov.: 32 AF XY: 0.304 AC XY: 175394 AN XY: 576508

Gnomad4 AFR exome AF: 0.305

Gnomad4 AMR exome AF: 0.203

Gnomad4 ASJ exome AF: 0.299

Gnomad4 EAS exome AF: 0.105

Gnomad4 SAS exome AF: 0.282

Gnomad4 FIN exome AF: 0.293

Gnomad4 NFE exome AF: 0.316

Gnomad4 OTH exome AF: 0.303

GnomAD4 genome AF: 0.280 AC: 41390 AN: 147946 Hom.: 5830 Cov.: 0 AF XY: 0.278 AC XY: 20016 AN XY: 72000

Gnomad4 AFR AF: 0.286

Gnomad4 AMR AF: 0.236

Gnomad4 ASJ AF: 0.277

Gnomad4 EAS AF: 0.0793

Gnomad4 SAS AF: 0.268

Gnomad4 FIN AF: 0.279

Gnomad4 NFE AF: 0.302

Gnomad4 OTH AF: 0.313

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Norman-Roberts syndrome;C4225327:Familial temporal lobe epilepsy 7 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Lissencephaly, Recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs35268159; hg19: chr7-103206001;