rs114684479

Variant names:

• chr7-103596518-G-T
• rs114684479
• NM_005045.4:c.3477C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005045.4(RELN):​c.3477C>A​(p.Asn1159Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 1,614,028 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (7 hom.)
• Consequence: RELN NM_005045.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:10
• Conservation: PhyloP100: 2.17
• Publications: 12 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.034067214).
• BP6: Variant 7-103596518-G-T is Benign according to our data. Variant chr7-103596518-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 281243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00144 (219/152290) while in subpopulation NFE AF = 0.00234 (159/68022). AF 95% confidence interval is 0.00204. There are 1 homozygotes in GnomAd4. There are 88 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 7 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.3477C>A	p.Asn1159Lys	missense	Exon 25 of 65	NP_005036.2
	RELN	NM_173054.3		c.3477C>A	p.Asn1159Lys	missense	Exon 25 of 64	NP_774959.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RELN	ENST00000428762.6	TSL:5 MANE Select	c.3477C>A	p.Asn1159Lys	missense	Exon 25 of 65	ENSP00000392423.1
	RELN	ENST00000424685.3	TSL:5	c.3477C>A	p.Asn1159Lys	missense	Exon 25 of 65	ENSP00000388446.3
	RELN	ENST00000343529.9	TSL:5	c.3477C>A	p.Asn1159Lys	missense	Exon 25 of 64	ENSP00000345694.5

Frequencies

GnomAD3 genomes AF: 0.00145 AC: 220 AN: 152172 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00234

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00163 AC: 408 AN: 251068 AF XY: 0.00186

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000926

Gnomad ASJ exome AF: 0.00387

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00229

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00174 AC: 2546 AN: 1461738 Hom.: 7 Cov.: 32 AF XY: 0.00181 AC XY: 1314 AN XY: 727180

African (AFR) AF: 0.000448 AC: 15 AN: 33474

American (AMR) AF: 0.00114 AC: 51 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00356 AC: 93 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00177 AC: 153 AN: 86258

European-Finnish (FIN) AF: 0.000168 AC: 9 AN: 53420

Middle Eastern (MID) AF: 0.00850 AC: 49 AN: 5764

European-Non Finnish (NFE) AF: 0.00183 AC: 2038 AN: 1111910

Other (OTH) AF: 0.00229 AC: 138 AN: 60380

GnomAD4 genome AF: 0.00144 AC: 219 AN: 152290 Hom.: 1 Cov.: 32 AF XY: 0.00118 AC XY: 88 AN XY: 74450

African (AFR) AF: 0.000409 AC: 17 AN: 41564

American (AMR) AF: 0.00137 AC: 21 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00234 AC: 159 AN: 68022

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00197 Hom.: 2

Bravo AF: 0.00149

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00349 AC: 30

ExAC AF: 0.00172 AC: 209

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00344

EpiControl AF: 0.00367

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	1	Norman-Roberts syndrome (1)
-	-	1	Norman-Roberts syndrome;C4225327:Familial temporal lobe epilepsy 7 (1)
-	-	1	RELN-related disorder (1)
1	-	-	Self-limited epilepsy with centrotemporal spikes (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.034	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.2
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.10
Sift	Benign	0.065	T
Sift4G	Uncertain	0.0060	D
Polyphen		0.99	D
Vest4		0.80
MutPred		0.44		Gain of ubiquitination at N1159 (P = 0.0219)
MVP		0.58
MPC		0.33
ClinPred		0.020	T
GERP RS		5.8
Varity_R		0.21
gMVP		0.72
Mutation Taster		=100/0	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: rs114684479; hg19: chr7-103236965;