7-103535518-C-T

Variant names:

• chr7-103535518-C-T
• rs362706
• NM_005045.4:c.7181-34G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005045.4(RELN):​c.7181-34G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.758 in 1,588,700 control chromosomes in the GnomAD database, including 457,478 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (42690 hom., cov: 32)
  • Exomes 𝑓: 0.76 (414788 hom.)
• Consequence: RELN NM_005045.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.117
• Publications: 5 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: Illumina, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P, PanelApp Australia
• 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

LOC105375435 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 7-103535518-C-T is Benign according to our data. Variant chr7-103535518-C-T is described in ClinVar as Benign. ClinVar VariationId is 259612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.756 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RELN	NM_005045.4	c.7181-34G>A		intron_variant	Intron 45 of 64	ENST00000428762.6	NP_005036.2
RELN	NM_173054.3	c.7181-34G>A		intron_variant	Intron 45 of 63		NP_774959.1
LOC105375435	XR_001745315.2	n.41+888C>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RELN	ENST00000428762.6	c.7181-34G>A		intron_variant	Intron 45 of 64	5	NM_005045.4	ENSP00000392423.1

Frequencies

GnomAD3 genomes AF: 0.749 AC: 113872 AN: 152020 Hom.: 42653 Cov.: 32

Gnomad AFR AF: 0.751

Gnomad AMI AF: 0.727

Gnomad AMR AF: 0.751

Gnomad ASJ AF: 0.767

Gnomad EAS AF: 0.607

Gnomad SAS AF: 0.681

Gnomad FIN AF: 0.751

Gnomad MID AF: 0.766

Gnomad NFE AF: 0.762

Gnomad OTH AF: 0.758

GnomAD2 exomes AF: 0.743 AC: 185329 AN: 249508 AF XY: 0.741

Gnomad AFR exome AF: 0.751

Gnomad AMR exome AF: 0.769

Gnomad ASJ exome AF: 0.766

Gnomad EAS exome AF: 0.611

Gnomad FIN exome AF: 0.753

Gnomad NFE exome AF: 0.763

Gnomad OTH exome AF: 0.745

GnomAD4 exome AF: 0.759 AC: 1089972 AN: 1436562 Hom.: 414788 Cov.: 25 AF XY: 0.756 AC XY: 541901 AN XY: 716444

African (AFR) AF: 0.752 AC: 24785 AN: 32942

American (AMR) AF: 0.767 AC: 34195 AN: 44602

Ashkenazi Jewish (ASJ) AF: 0.766 AC: 19888 AN: 25948

East Asian (EAS) AF: 0.577 AC: 22827 AN: 39560

South Asian (SAS) AF: 0.700 AC: 59980 AN: 85666

European-Finnish (FIN) AF: 0.753 AC: 40020 AN: 53160

Middle Eastern (MID) AF: 0.751 AC: 4298 AN: 5722

European-Non Finnish (NFE) AF: 0.770 AC: 839274 AN: 1089454

Other (OTH) AF: 0.751 AC: 44705 AN: 59508

GnomAD4 genome AF: 0.749 AC: 113971 AN: 152138 Hom.: 42690 Cov.: 32 AF XY: 0.746 AC XY: 55445 AN XY: 74362

African (AFR) AF: 0.751 AC: 31182 AN: 41502

American (AMR) AF: 0.751 AC: 11481 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.767 AC: 2661 AN: 3470

East Asian (EAS) AF: 0.607 AC: 3136 AN: 5170

South Asian (SAS) AF: 0.681 AC: 3291 AN: 4830

European-Finnish (FIN) AF: 0.751 AC: 7936 AN: 10574

Middle Eastern (MID) AF: 0.772 AC: 227 AN: 294

European-Non Finnish (NFE) AF: 0.762 AC: 51795 AN: 67994

Other (OTH) AF: 0.758 AC: 1600 AN: 2112

Alfa AF: 0.758 Hom.: 15038

Bravo AF: 0.751

Asia WGS AF: 0.647 AC: 2251 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Norman-Roberts syndrome Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.3
DANN	Benign	0.60
PhyloP100		-0.12
Mutation Taster		=100/0	polymorphism (auto)

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: rs362706; hg19: chr7-103175965;