7-83405499-T-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_012431.3(SEMA3E):c.949A>T(p.Thr317Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000146 in 1,612,930 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T317T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

SEMA3E
NM_012431.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 4.78

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: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 7 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA3E	NM_012431.3 link	c.949A>T	p.Thr317Ser	missense_variant	Exon 9 of 17	ENST00000643230.2	NP_036563.1	O15041-1
SEMA3E	NM_001178129.2 link	c.769A>T	p.Thr257Ser	missense_variant	Exon 9 of 17		NP_001171600.1	O15041-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA3E	ENST00000643230.2 link	c.949A>T	p.Thr317Ser	missense_variant	Exon 9 of 17	NM_012431.3	ENSP00000496491.1	O15041-1
SEMA3E	ENST00000642232.1 link	c.949A>T	p.Thr317Ser	missense_variant	Exon 9 of 17		ENSP00000494064.1	A0A2R8YCX5
SEMA3E	ENST00000643441.1 link	n.934A>T		non_coding_transcript_exon_variant	Exon 9 of 17

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152020

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000103

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000439

AC:

AN:

250812

AF XY:

0.0000369

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000882

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000156

AC:

228

AN:

1460910

Hom.:

Cov.:

AF XY:

0.000157

AC XY:

114

AN XY:

726760

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33442

American (AMR)

AF:

0.00

AC:

AN:

44632

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26102

East Asian (EAS)

AF:

0.00

AC:

AN:

39646

South Asian (SAS)

AF:

0.00

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.000200

AC:

222

AN:

1111362

Other (OTH)

AF:

0.0000829

AC:

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.441

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152020

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74232

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41420

American (AMR)

AF:

0.00

AC:

AN:

15218

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

67974

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000602

Hom.:

ExAC

AF:

0.0000577

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 21, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.949A>T (p.T317S) alteration is located in exon 9 (coding exon 9) of the SEMA3E gene. This alteration results from a A to T substitution at nucleotide position 949, causing the threonine (T) at amino acid position 317 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

CHARGE syndrome

Uncertain:1

Jan 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 317 of the SEMA3E protein (p.Thr317Ser). This variant is present in population databases (rs752718717, gnomAD 0.01%). 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: 459539). 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 with a negative predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. -

CHARGE syndrome;C0342384:Hypogonadotropic hypogonadism 7 with or without anosmia

Uncertain:1

Nov 05, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

SEMA3E-related disorder

Uncertain:1

Jun 08, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The SEMA3E c.949A>T variant is predicted to result in the amino acid substitution p.Thr317Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0085% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is predicted to alter splicing based on available splicing prediction software (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751). However, the use of computer prediction software is not equivalent to functional evidence. 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

0.080

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.46

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

T;T;.;.

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.76

.;T;T;T

M_CAP

Benign

0.0075

MetaRNN

Benign

0.28

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

L;L;.;.

PhyloP100

4.8

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.9

N;.;N;.

REVEL

Benign

0.17

Sift

Benign

0.32

T;.;T;.

Sift4G

Benign

0.31

T;.;T;.

Polyphen

0.91

P;P;.;.

Vest4

0.41

MutPred

0.50

Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);.;Gain of relative solvent accessibility (P = 0.0479);

MVP

0.60

MPC

0.18

ClinPred

0.32

GERP RS

5.9

Varity_R

0.14

gMVP

0.32

Mutation Taster

=84/16

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.42

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.42

Position offset: -5

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over