chr7-83392585-C-T

Variant names:

• chr7-83392585-C-T
• rs769248913
• NM_012431.3:c.1637G>A

Variant summary

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

The NM_012431.3(SEMA3E):​c.1637G>A​(p.Arg546Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000806 in 1,613,368 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: SEMA3E NM_012431.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.14

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA3E	NM_012431.3	c.1637G>A	p.Arg546Gln	missense_variant	Exon 14 of 17	ENST00000643230.2	NP_036563.1
SEMA3E	NM_001178129.2	c.1457G>A	p.Arg486Gln	missense_variant	Exon 14 of 17		NP_001171600.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEMA3E	ENST00000643230.2	c.1637G>A	p.Arg546Gln	missense_variant	Exon 14 of 17		NM_012431.3	ENSP00000496491.1
SEMA3E	ENST00000642232.1	c.1637G>A	p.Arg546Gln	missense_variant	Exon 14 of 17			ENSP00000494064.1
SEMA3E	ENST00000643441.1	n.1622G>A		non_coding_transcript_exon_variant	Exon 14 of 17

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 151770 Hom.: 0 Cov.: 31

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461598 Hom.: 0 Cov.: 34 AF XY: 0.00000550 AC XY: 4 AN XY: 727102

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 151770 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74086

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

CHARGE syndrome Uncertain:2

Jan 23, 2025

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 glutamine, which is neutral and polar, at codon 546 of the SEMA3E protein (p.Arg546Gln). This variant is not present in population databases (gnomAD no frequency). 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: 529119). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt SEMA3E protein function with a negative predictive value of 80%. 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. -

Dec 04, 2019

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.0040	T
BayesDel_noAF	Benign	-0.24
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.50	D;D;.;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.97	.;D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.64	D;D;D;D
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.6	M;M;.;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.7	D;.;D;.
REVEL	Benign	0.25
Sift	Uncertain	0.0050	D;.;D;.
Sift4G	Uncertain	0.036	D;.;D;.
Polyphen		1.0	D;D;.;.
Vest4		0.63
MutPred		0.58		Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);.;Loss of sheet (P = 0.0181);
MVP		0.72
MPC		0.23
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.50
gMVP		0.59

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

Other links and lift over

dbSNP: rs769248913; hg19: chr7-83021901; COSMIC: COSV57100007;