rs115577014

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_005045.4(RELN):​c.4337A>T​(p.Asn1446Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1446S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

RELN
NM_005045.4 missense

Scores

8
11

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.77
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RELN. . Gene score misZ 2.2497 (greater than the threshold 3.09). Trascript score misZ 4.2638 (greater than threshold 3.09). GenCC has associacion of gene with ankylosing spondylitis, lissencephaly with cerebellar hypoplasia, Norman-Roberts syndrome, complex neurodevelopmental disorder, autosomal dominant epilepsy with auditory features, familial temporal lobe epilepsy 7.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RELNNM_005045.4 linkuse as main transcriptc.4337A>T p.Asn1446Ile missense_variant 30/65 ENST00000428762.6
RELNNM_173054.3 linkuse as main transcriptc.4337A>T p.Asn1446Ile missense_variant 30/64

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RELNENST00000428762.6 linkuse as main transcriptc.4337A>T p.Asn1446Ile missense_variant 30/655 NM_005045.4 P5P78509-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461862
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
727238
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.19
BayesDel_addAF
Benign
-0.097
T
BayesDel_noAF
Benign
-0.38
CADD
Uncertain
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.14
T;.;.
Eigen
Uncertain
0.35
Eigen_PC
Uncertain
0.36
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.90
D;D;D
M_CAP
Benign
0.020
T
MetaRNN
Uncertain
0.72
D;D;D
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.7
L;L;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Benign
0.45
T
PROVEAN
Benign
-2.2
N;N;N
REVEL
Benign
0.17
Sift
Uncertain
0.028
D;D;D
Sift4G
Uncertain
0.013
D;D;D
Polyphen
0.96
D;P;.
Vest4
0.86
MutPred
0.47
Loss of disorder (P = 0.0429);Loss of disorder (P = 0.0429);Loss of disorder (P = 0.0429);
MVP
0.20
MPC
0.69
ClinPred
0.91
D
GERP RS
5.5
Varity_R
0.33
gMVP
0.52

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.060
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs115577014; hg19: chr7-103214713; API