rs1167948188

chr7-103630182-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_005045.4(RELN):c.2466-6C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000572 in 1,123,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00057 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RELN NM_005045.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00009665
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.560

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 7-103630182-G-A is Benign according to our data. Variant chr7-103630182-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 475952.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-103630182-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000572 (643/1123646) while in subpopulation AFR AF= 0.00366 (92/25140). AF 95% confidence interval is 0.00305. There are 0 homozygotes in gnomad4_exome. There are 306 alleles in male gnomad4_exome subpopulation. Median coverage is 24. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RELN	NM_005045.4	c.2466-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000428762.6
RELN	NM_173054.3	c.2466-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RELN	ENST00000428762.6	c.2466-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_005045.4	P5

Frequencies

GnomAD3 genomes AF: 0.00 AC: 16 AN: 138570 Hom.: 0 Cov.: 32 FAILED QC

Gnomad AFR AF: 0.0000531

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: 0.00101

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000787

Gnomad OTH AF: 0.000538

GnomAD3 exomes AF: 0.00286 AC: 290 AN: 101368 Hom.: 0 AF XY: 0.00279 AC XY: 152 AN XY: 54572

Gnomad AFR exome AF: 0.00332

Gnomad AMR exome AF: 0.000915

Gnomad ASJ exome AF: 0.00624

Gnomad EAS exome AF: 0.000917

Gnomad SAS exome AF: 0.00226

Gnomad FIN exome AF: 0.00185

Gnomad NFE exome AF: 0.00355

Gnomad OTH exome AF: 0.00485

GnomAD4 exome AF: 0.000572 AC: 643 AN: 1123646 Hom.: 0 Cov.: 24 AF XY: 0.000547 AC XY: 306 AN XY: 559714

Gnomad4 AFR exome AF: 0.00366

Gnomad4 AMR exome AF: 0.00331

Gnomad4 ASJ exome AF: 0.00131

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.000806

Gnomad4 FIN exome AF: 0.000951

Gnomad4 NFE exome AF: 0.000335

Gnomad4 OTH exome AF: 0.000696

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000115 AC: 16 AN: 138570 Hom.: 0 Cov.: 32 AF XY: 0.0000746 AC XY: 5 AN XY: 67002

Gnomad4 AFR AF: 0.0000531

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00101

Gnomad4 NFE AF: 0.0000787

Gnomad4 OTH AF: 0.000538

Alfa AF: 0.00818 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Feb 14, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	1.9
Dann	Benign	0.48

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000097
dbscSNV1_RF	Benign	0.0
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: rs1167948188; hg19: chr7-103270629;