rs756854888
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2BP4BS1_Supporting
The NM_005045.4(RELN):āc.9753G>Cā(p.Glu3251Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000824 in 1,613,926 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E3251K) has been classified as Uncertain significance.
Frequency
Consequence
NM_005045.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RELN | NM_005045.4 | c.9753G>C | p.Glu3251Asp | missense_variant | 60/65 | ENST00000428762.6 | |
SLC26A5-AS1 | NR_110141.1 | n.1366-14652C>G | intron_variant, non_coding_transcript_variant | ||||
RELN | NM_173054.3 | c.9753G>C | p.Glu3251Asp | missense_variant | 60/64 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RELN | ENST00000428762.6 | c.9753G>C | p.Glu3251Asp | missense_variant | 60/65 | 5 | NM_005045.4 | P5 | |
SLC26A5-AS1 | ENST00000422488.1 | n.1366-14652C>G | intron_variant, non_coding_transcript_variant | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152172Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000359 AC: 9AN: 250942Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135660
GnomAD4 exome AF: 0.0000883 AC: 129AN: 1461754Hom.: 0 Cov.: 32 AF XY: 0.0000743 AC XY: 54AN XY: 727168
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152172Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74342
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 23, 2021 | The c.9753G>C (p.E3251D) alteration is located in exon 60 (coding exon 60) of the RELN gene. This alteration results from a G to C substitution at nucleotide position 9753, causing the glutamic acid (E) at amino acid position 3251 to be replaced by an aspartic acid (D). The p.E3251D alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Norman-Roberts syndrome;C4225327:Familial temporal lobe epilepsy 7 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 16, 2023 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RELN protein function. ClinVar contains an entry for this variant (Variation ID: 568369). This variant has not been reported in the literature in individuals affected with RELN-related conditions. This variant is present in population databases (rs756854888, gnomAD 0.007%). This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 3251 of the RELN protein (p.Glu3251Asp). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at