rs148649507
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Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2
The NM_012431.3(SEMA3E):c.2152G>A(p.Gly718Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000102 in 1,613,938 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 0.000099 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00010 ( 0 hom. )
Consequence
SEMA3E
NM_012431.3 missense
NM_012431.3 missense
Scores
2
7
10
Clinical Significance
Conservation
PhyloP100: 7.40
Genes affected
SEMA3E (HGNC:10727): (semaphorin 3E) Semaphorins are a large family of conserved secreted and membrane associated proteins which possess a semaphorin (Sema) domain and a PSI domain (found in plexins, semaphorins and integrins) in the N-terminal extracellular portion. Based on sequence and structural similarities, semaphorins are put into eight classes: invertebrates contain classes 1 and 2, viruses have class V, and vertebrates contain classes 3-7. Semaphorins serve as axon guidance ligands via multimeric receptor complexes, some (if not all) containing plexin proteins. This gene encodes a class 4 semaphorin. This gene encodes a class 3 semaphorin. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, May 2010]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -7 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.2637493).
BP6
Variant 7-83367762-C-T is Benign according to our data. Variant chr7-83367762-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 459538.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
BS2
High AC in GnomAd4 at 15 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SEMA3E | NM_012431.3 | c.2152G>A | p.Gly718Ser | missense_variant | 17/17 | ENST00000643230.2 | |
SEMA3E | NM_001178129.2 | c.1972G>A | p.Gly658Ser | missense_variant | 17/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SEMA3E | ENST00000643230.2 | c.2152G>A | p.Gly718Ser | missense_variant | 17/17 | NM_012431.3 | P1 | ||
SEMA3E | ENST00000643441.1 | n.2137G>A | non_coding_transcript_exon_variant | 17/17 |
Frequencies
GnomAD3 genomes AF: 0.0000986 AC: 15AN: 152058Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000111 AC: 28AN: 251478Hom.: 0 AF XY: 0.000125 AC XY: 17AN XY: 135910
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GnomAD4 exome AF: 0.000102 AC: 149AN: 1461880Hom.: 0 Cov.: 32 AF XY: 0.000105 AC XY: 76AN XY: 727236
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GnomAD4 genome AF: 0.0000986 AC: 15AN: 152058Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8AN XY: 74262
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
CHARGE syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 06, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 718 of the SEMA3E protein (p.Gly718Ser). This variant is present in population databases (rs148649507, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with SEMA3E-related conditions. ClinVar contains an entry for this variant (Variation ID: 459538). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 05, 2019 | - - |
SEMA3E-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 19, 2022 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
.;T;T
M_CAP
Benign
D
MetaRNN
Benign
T;T;T
MetaSVM
Uncertain
T
MutationAssessor
Benign
L;L;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.;N
REVEL
Uncertain
Sift
Benign
T;.;T
Sift4G
Benign
T;.;T
Polyphen
D;D;.
Vest4
MVP
MPC
ClinPred
T
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Varity_R
gMVP
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