7-83961733-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_006080.3(SEMA3A):​c.1954G>A​(p.Val652Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000979 in 1,613,878 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00010 ( 3 hom. )

Consequence

SEMA3A
NM_006080.3 missense

Scores

6
13

Clinical Significance

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

Conservation

PhyloP100: 4.01
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0872508).
BS2
High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SEMA3ANM_006080.3 linkuse as main transcriptc.1954G>A p.Val652Met missense_variant 17/17 ENST00000265362.9
SEMA3AXM_005250110.4 linkuse as main transcriptc.1954G>A p.Val652Met missense_variant 20/20
SEMA3AXM_047419751.1 linkuse as main transcriptc.1954G>A p.Val652Met missense_variant 21/21

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SEMA3AENST00000265362.9 linkuse as main transcriptc.1954G>A p.Val652Met missense_variant 17/171 NM_006080.3 P1
SEMA3AENST00000436949.5 linkuse as main transcriptc.1954G>A p.Val652Met missense_variant 18/185 P1

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152128
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000828
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000195
AC:
49
AN:
251076
Hom.:
0
AF XY:
0.000251
AC XY:
34
AN XY:
135698
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00150
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.000105
AC:
153
AN:
1461632
Hom.:
3
Cov.:
33
AF XY:
0.000149
AC XY:
108
AN XY:
727126
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00173
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000662
GnomAD4 genome
AF:
0.0000328
AC:
5
AN:
152246
Hom.:
0
Cov.:
32
AF XY:
0.0000672
AC XY:
5
AN XY:
74416
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000829
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113
ExAC
AF:
0.000198
AC:
24

ClinVar

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

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 04, 2023The c.1954G>A (p.V652M) alteration is located in exon 17 (coding exon 17) of the SEMA3A gene. This alteration results from a G to A substitution at nucleotide position 1954, causing the valine (V) at amino acid position 652 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
SEMA3A-related disorder Benign:1
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesFeb 05, 2024This 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.40
T
BayesDel_noAF
Benign
-0.38
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.20
T;T
Eigen
Uncertain
0.45
Eigen_PC
Uncertain
0.54
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.94
.;D
M_CAP
Benign
0.023
T
MetaRNN
Benign
0.087
T;T
MetaSVM
Benign
-0.89
T
MutationAssessor
Benign
1.8
L;L
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.55
T
PROVEAN
Benign
-0.050
N;N
REVEL
Benign
0.21
Sift
Benign
0.082
T;T
Sift4G
Benign
0.20
T;T
Polyphen
0.79
P;P
Vest4
0.27
MutPred
0.45
Gain of catalytic residue at V652 (P = 0.1726);Gain of catalytic residue at V652 (P = 0.1726);
MVP
0.23
MPC
0.87
ClinPred
0.048
T
GERP RS
6.2
Varity_R
0.085
gMVP
0.44

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: rs549486833; hg19: chr7-83591049; API