7-83394299-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_012431.3(SEMA3E):c.1498C>G(p.Arg500Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,982 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R500W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SEMA3E
NM_012431.3 missense, splice_region

Scores

Splicing: ADA: 0.001646

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.11

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
Kallmann syndrome
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
CHARGE syndrome
Inheritance: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

SEMA3E links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA3E	NM_012431.3 link	c.1498C>G	p.Arg500Gly	missense_variant, splice_region_variant	Exon 13 of 17	ENST00000643230.2	NP_036563.1	O15041-1
SEMA3E	NM_001178129.2 link	c.1318C>G	p.Arg440Gly	missense_variant, splice_region_variant	Exon 13 of 17		NP_001171600.1	O15041-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA3E	ENST00000643230.2 link	c.1498C>G	p.Arg500Gly	missense_variant, splice_region_variant	Exon 13 of 17	NM_012431.3	ENSP00000496491.1	O15041-1
SEMA3E	ENST00000642232.1 link	c.1498C>G	p.Arg500Gly	missense_variant, splice_region_variant	Exon 13 of 17		ENSP00000494064.1	A0A2R8YCX5
SEMA3E	ENST00000643441.1 link	n.1483C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 13 of 17

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1460982

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726818

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33456

American (AMR)

AF:

0.00

AC:

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39612

South Asian (SAS)

AF:

0.00

AC:

AN:

86234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53136

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111630

Other (OTH)

AF:

0.00

AC:

AN:

60350

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.58

D;D;.;.

Eigen

Benign

-0.071

Eigen_PC

Benign

-0.015

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.97

.;D;D;D

M_CAP

Benign

0.053

MetaRNN

Uncertain

0.63

D;D;D;D

MetaSVM

Benign

-1.1

MutationAssessor

Pathogenic

3.3

M;M;.;.

PhyloP100

1.1

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-5.1

D;.;D;.

REVEL

Benign

0.24

Sift

Uncertain

0.0010

D;.;D;.

Sift4G

Uncertain

0.0020

D;.;D;.

Polyphen

0.26

B;B;.;.

Vest4

0.82

MutPred

0.59

Loss of solvent accessibility (P = 0.0329);Loss of solvent accessibility (P = 0.0329);.;Loss of solvent accessibility (P = 0.0329);

MVP

0.57

MPC

0.79

ClinPred

0.99

GERP RS

3.6

Varity_R

0.89

gMVP

0.48

Mutation Taster

=25/75

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0016

dbscSNV1_RF

Benign

0.028

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over