chr7-83367614-C-A

Variant names:

• chr7-83367614-C-A
• rs746701899
• NM_012431.3:c.2300G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BS2

The NM_012431.3(SEMA3E):​c.2300G>T​(p.Arg767Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SEMA3E NM_012431.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 5.18
• Publications: 3 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS2: High AC in GnomAdExome4 at 5 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA3E	NM_012431.3	c.2300G>T	p.Arg767Leu	missense_variant	Exon 17 of 17	ENST00000643230.2	NP_036563.1
SEMA3E	NM_001178129.2	c.2120G>T	p.Arg707Leu	missense_variant	Exon 17 of 17		NP_001171600.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEMA3E	ENST00000643230.2	c.2300G>T	p.Arg767Leu	missense_variant	Exon 17 of 17		NM_012431.3	ENSP00000496491.1
SEMA3E	ENST00000643441.1	n.2285G>T		non_coding_transcript_exon_variant	Exon 17 of 17

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461870 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111988

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

CHARGE syndrome Uncertain:1

Apr 29, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 767 of the SEMA3E protein (p.Arg767Leu). This variant is present in population databases (rs746701899, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with SEMA3E-related conditions. 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. 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. -

SEMA3E-related disorder Uncertain:1

May 16, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SEMA3E c.2300G>T variant is predicted to result in the amino acid substitution p.Arg767Leu. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. 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	Pathogenic	0.76
BayesDel_addAF	Benign	-0.012	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D;D;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	.;D;D
M_CAP	Benign	0.048	D
MetaRNN	Uncertain	0.59	D;D;D
MetaSVM	Benign	-0.53	T
MutationAssessor	Pathogenic	3.0	M;M;.
PhyloP100		5.2
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.3	D;.;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0020	D;.;D
Sift4G	Uncertain	0.0050	D;.;D
Polyphen		1.0	D;D;.
Vest4		0.45
MutPred		0.56		Loss of MoRF binding (P = 2e-04);Loss of MoRF binding (P = 2e-04);.;
MVP		0.86
MPC		0.77
ClinPred		0.97	D
GERP RS		5.6
Varity_R		0.51
gMVP		0.60
Mutation Taster		=59/41	polymorphism

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

Other links and lift over

dbSNP: rs746701899; hg19: chr7-82996930;