chr7-83961487-G-A
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Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_006080.3(SEMA3A):c.2200C>T(p.Arg734Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,613,840 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000018 ( 0 hom. )
Consequence
SEMA3A
NM_006080.3 missense
NM_006080.3 missense
Scores
2
11
6
Clinical Significance
Conservation
PhyloP100: 1.70
Genes affected
SEMA3A (HGNC:10723): (semaphorin 3A) This gene is a member of the semaphorin family and encodes a protein with an Ig-like C2-type (immunoglobulin-like) domain, a PSI domain and a Sema domain. This secreted protein can function as either a chemorepulsive agent, inhibiting axonal outgrowth, or as a chemoattractive agent, stimulating the growth of apical dendrites. In both cases, the protein is vital for normal neuronal pattern development. Increased expression of this protein is associated with schizophrenia and is seen in a variety of human tumor cell lines. Also, aberrant release of this protein is associated with the progression of Alzheimer's disease. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -4 ACMG points.
BS2
High AC in GnomAdExome4 at 26 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SEMA3A | NM_006080.3 | c.2200C>T | p.Arg734Trp | missense_variant | 17/17 | ENST00000265362.9 | |
SEMA3A | XM_005250110.4 | c.2200C>T | p.Arg734Trp | missense_variant | 20/20 | ||
SEMA3A | XM_047419751.1 | c.2200C>T | p.Arg734Trp | missense_variant | 21/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SEMA3A | ENST00000265362.9 | c.2200C>T | p.Arg734Trp | missense_variant | 17/17 | 1 | NM_006080.3 | P1 | |
SEMA3A | ENST00000436949.5 | c.2200C>T | p.Arg734Trp | missense_variant | 18/18 | 5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152064Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251198Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135750
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GnomAD4 exome AF: 0.0000178 AC: 26AN: 1461776Hom.: 0 Cov.: 30 AF XY: 0.0000151 AC XY: 11AN XY: 727192
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152064Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74276
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 13, 2023 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 734 of the SEMA3A protein (p.Arg734Trp). This variant is present in population databases (rs776695769, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with SEMA3A-related conditions. ClinVar contains an entry for this variant (Variation ID: 2136550). 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. Experimental studies have shown that this missense change affects SEMA3A function (PMID: 24963029). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2022 | - - |
SEMA3A-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 02, 2024 | The SEMA3A c.2200C>T variant is predicted to result in the amino acid substitution p.Arg734Trp. To our knowledge, this variant has not been reported in the literature in individuals with SEMA3A-related disease. This variant is reported in 0.016% of alleles in individuals of East Asian descent in gnomAD, which is more common than expected for a primary cause of disease. Although we suspect this variant may be benign, at this time, the clinical significance is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Pathogenic
DEOGEN2
Uncertain
D;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D
M_CAP
Benign
T
MetaRNN
Uncertain
D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D
REVEL
Benign
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
D;D
Vest4
MutPred
Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);
MVP
MPC
ClinPred
D
GERP RS
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