chr7-103483818-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4_StrongBS1_Supporting

The NM_005045.4(RELN):ā€‹c.10016T>Cā€‹(p.Met3339Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000359 in 1,613,936 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M3339L) has been classified as Likely benign.

Frequency

Genomes: š‘“ 0.00016 ( 0 hom., cov: 32)
Exomes š‘“: 0.000023 ( 0 hom. )

Consequence

RELN
NM_005045.4 missense

Scores

19

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 1.46
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]
SLC26A5-AS1 (HGNC:55680): (SLC26A5 antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 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=0.03701806).
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000164 (25/152262) while in subpopulation AFR AF= 0.000579 (24/41472). AF 95% confidence interval is 0.000399. There are 0 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RELNNM_005045.4 linkuse as main transcriptc.10016T>C p.Met3339Thr missense_variant 62/65 ENST00000428762.6
SLC26A5-AS1NR_110141.1 linkuse as main transcriptn.1366-20586A>G intron_variant, non_coding_transcript_variant
RELNNM_173054.3 linkuse as main transcriptc.10016T>C p.Met3339Thr missense_variant 62/64

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RELNENST00000428762.6 linkuse as main transcriptc.10016T>C p.Met3339Thr missense_variant 62/655 NM_005045.4 P5P78509-1
SLC26A5-AS1ENST00000422488.1 linkuse as main transcriptn.1366-20586A>G intron_variant, non_coding_transcript_variant 1

Frequencies

GnomAD3 genomes
AF:
0.000164
AC:
25
AN:
152262
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000579
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000359
AC:
9
AN:
250708
Hom.:
0
AF XY:
0.0000369
AC XY:
5
AN XY:
135446
show subpopulations
Gnomad AFR exome
AF:
0.000431
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000226
AC:
33
AN:
1461674
Hom.:
0
Cov.:
32
AF XY:
0.0000248
AC XY:
18
AN XY:
727148
show subpopulations
Gnomad4 AFR exome
AF:
0.000209
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000198
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.000164
AC:
25
AN:
152262
Hom.:
0
Cov.:
32
AF XY:
0.000148
AC XY:
11
AN XY:
74390
show subpopulations
Gnomad4 AFR
AF:
0.000579
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000329
Hom.:
0
Bravo
AF:
0.000193
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000330
AC:
4
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:3
Uncertain significance, criteria provided, single submitterclinical testingGeneDxApr 30, 2019Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function -
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Feb 28, 2014- -
Uncertain significance, criteria provided, single submitterclinical testingAthena DiagnosticsJun 06, 2018- -
Norman-Roberts syndrome;C4225327:Familial temporal lobe epilepsy 7 Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeJan 12, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.046
BayesDel_addAF
Benign
-0.55
T
BayesDel_noAF
Benign
-0.68
CADD
Benign
0.16
DANN
Benign
0.59
DEOGEN2
Benign
0.036
T;.;.
Eigen
Benign
-1.3
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.016
N
LIST_S2
Benign
0.51
T;T;T
M_CAP
Benign
0.0018
T
MetaRNN
Benign
0.037
T;T;T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
0.0
N;N;.
MutationTaster
Benign
1.0
N;N;N
PrimateAI
Benign
0.24
T
PROVEAN
Benign
1.0
N;N;N
REVEL
Benign
0.018
Sift
Benign
0.34
T;T;T
Sift4G
Benign
0.40
T;T;T
Polyphen
0.0
B;B;.
Vest4
0.061
MVP
0.043
MPC
0.34
ClinPred
0.012
T
GERP RS
2.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.033
gMVP
0.21

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

Publications

LitVar

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

Other links and lift over

dbSNP: rs150638029; hg19: chr7-103124265; API