rs752774852

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_012431.3(SEMA3E):c.1303C>G(p.Gln435Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000744 in 1,613,864 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

SEMA3E
NM_012431.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 6.59

Variant links:

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]

SEMA3E links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAdExome at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEMA3E	NM_012431.3 linkuse as main transcript	c.1303C>G	p.Gln435Glu	missense_variant	11/17	ENST00000643230.2
SEMA3E	NM_001178129.2 linkuse as main transcript	c.1123C>G	p.Gln375Glu	missense_variant	11/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Appris	UniProt
SEMA3E	ENST00000643230.2 linkuse as main transcript	c.1303C>G	p.Gln435Glu	missense_variant	11/17	NM_012431.3	P1	O15041-1
SEMA3E	ENST00000642232.1 linkuse as main transcript	c.1303C>G	p.Gln435Glu	missense_variant	11/17
SEMA3E	ENST00000643441.1 linkuse as main transcript	n.1288C>G		non_coding_transcript_exon_variant	11/17

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

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:

0.0000199

AC:

AN:

251258

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135786

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

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:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461776

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727172

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152088

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74288

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.0000656

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

Bravo

AF:

0.0000151

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

CHARGE syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 20, 2022

This variant is present in population databases (rs752774852, gnomAD 0.01%). This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 435 of the SEMA3E protein (p.Gln435Glu). This variant has not been reported in the literature in individuals affected with SEMA3E-related conditions. 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 SEMA3E protein function. ClinVar contains an entry for this variant (Variation ID: 529115). -

SEMA3E-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 08, 2024

The SEMA3E c.1303C>G variant is predicted to result in the amino acid substitution p.Gln435Glu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.014% of alleles in individuals of Latino descent in gnomAD, which may be too common to be a primary cause of disease. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.00092

BayesDel_noAF

Uncertain

0.020

Cadd

Pathogenic

Dann

Uncertain

0.99

DEOGEN2

Benign

0.27

T;T;.;.

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.98

M_CAP

Benign

0.032

MetaRNN

Uncertain

0.72

D;D;D;D

MetaSVM

Benign

-0.83

MutationAssessor

Pathogenic

3.6

H;H;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-2.4

N;.;N;.

REVEL

Uncertain

0.36

Sift

Uncertain

0.0050

D;.;D;.

Sift4G

Uncertain

0.027

D;.;D;.

Polyphen

1.0

D;D;.;.

Vest4

0.33

MutPred

0.65

Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);.;Gain of sheet (P = 0.0827);

MVP

0.79

MPC

0.69

ClinPred

0.97

GERP RS

5.5

Varity_R

0.86

gMVP

0.70

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over