7-103776611-G-A
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Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4BP6BS1
The NM_005045.4(RELN):c.490C>T(p.Arg164Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000062 in 1,613,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000064 ( 0 hom. )
Consequence
RELN
NM_005045.4 missense
NM_005045.4 missense
Scores
1
5
13
Clinical Significance
Conservation
PhyloP100: 2.77
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 Likely_benign. Variant got -5 ACMG points.
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.
BP4
Computational evidence support a benign effect (MetaRNN=0.40941373).
BP6
Variant 7-103776611-G-A is Benign according to our data. Variant chr7-103776611-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 475968.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
BS1
Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000636 (93/1461742) while in subpopulation SAS AF= 0.000174 (15/86252). AF 95% confidence interval is 0.000107. There are 0 homozygotes in gnomad4_exome. There are 46 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RELN | NM_005045.4 | c.490C>T | p.Arg164Trp | missense_variant | 4/65 | ENST00000428762.6 | NP_005036.2 | |
RELN | NM_173054.3 | c.490C>T | p.Arg164Trp | missense_variant | 4/64 | NP_774959.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RELN | ENST00000428762.6 | c.490C>T | p.Arg164Trp | missense_variant | 4/65 | 5 | NM_005045.4 | ENSP00000392423.1 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152118Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000677 AC: 17AN: 251220Hom.: 0 AF XY: 0.0000810 AC XY: 11AN XY: 135768
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GnomAD4 exome AF: 0.0000636 AC: 93AN: 1461742Hom.: 0 Cov.: 31 AF XY: 0.0000633 AC XY: 46AN XY: 727170
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GnomAD4 genome AF: 0.0000460 AC: 7AN: 152118Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4AN XY: 74308
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 24, 2024 | In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign in association with RELN-related disorder to our knowledge; This variant is associated with the following publications: (PMID: 33004838) - |
Norman-Roberts syndrome;C4225327:Familial temporal lobe epilepsy 7 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 19, 2023 | - - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Uncertain
D;D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;L;.
PrimateAI
Uncertain
T
PROVEAN
Uncertain
N;N;N
REVEL
Benign
Sift
Pathogenic
D;D;D
Sift4G
Uncertain
D;D;D
Polyphen
D;P;.
Vest4
MutPred
Loss of loop (P = 0.0804);Loss of loop (P = 0.0804);Loss of loop (P = 0.0804);
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at