rs61729612

chr7-83408415-C-Gchr7-83408415-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_012431.3(SEMA3E):c.623G>C(p.Arg208Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.118 in 1,613,448 control chromosomes in the GnomAD database, including 11,976 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (985 hom., cov: 33)
  • Exomes 𝑓: 0.12 (10991 hom.)
• Consequence: SEMA3E NM_012431.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.678

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017450154).
• BP6: Variant 7-83408415-C-G is Benign according to our data. Variant chr7-83408415-C-G is described in ClinVar as [Benign]. Clinvar id is 260256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.138 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEMA3E	NM_012431.3	c.623G>C	p.Arg208Pro	missense_variant	6/17	ENST00000643230.2
SEMA3E	NM_001178129.2	c.443G>C	p.Arg148Pro	missense_variant	6/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEMA3E	ENST00000643230.2	c.623G>C	p.Arg208Pro	missense_variant	6/17		NM_012431.3	P1

Frequencies

GnomAD3 genomes AF: 0.110 AC: 16773 AN: 152102 Hom.: 984 Cov.: 33

Gnomad AFR AF: 0.0770

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.119

Gnomad ASJ AF: 0.244

Gnomad EAS AF: 0.147

Gnomad SAS AF: 0.0651

Gnomad FIN AF: 0.105

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.122

Gnomad OTH AF: 0.119

GnomAD3 exomes AF: 0.117 AC: 29289 AN: 250778 Hom.: 1924 AF XY: 0.116 AC XY: 15744 AN XY: 135542

Gnomad AFR exome AF: 0.0739

Gnomad AMR exome AF: 0.128

Gnomad ASJ exome AF: 0.237

Gnomad EAS exome AF: 0.120

Gnomad SAS exome AF: 0.0652

Gnomad FIN exome AF: 0.112

Gnomad NFE exome AF: 0.124

Gnomad OTH exome AF: 0.114

GnomAD4 exome AF: 0.119 AC: 173892 AN: 1461232 Hom.: 10991 Cov.: 32 AF XY: 0.118 AC XY: 85767 AN XY: 726894

Gnomad4 AFR exome AF: 0.0753

Gnomad4 AMR exome AF: 0.123

Gnomad4 ASJ exome AF: 0.237

Gnomad4 EAS exome AF: 0.166

Gnomad4 SAS exome AF: 0.0662

Gnomad4 FIN exome AF: 0.110

Gnomad4 NFE exome AF: 0.120

Gnomad4 OTH exome AF: 0.124

GnomAD4 genome AF: 0.110 AC: 16777 AN: 152216 Hom.: 985 Cov.: 33 AF XY: 0.111 AC XY: 8257 AN XY: 74400

Gnomad4 AFR AF: 0.0770

Gnomad4 AMR AF: 0.119

Gnomad4 ASJ AF: 0.244

Gnomad4 EAS AF: 0.146

Gnomad4 SAS AF: 0.0654

Gnomad4 FIN AF: 0.105

Gnomad4 NFE AF: 0.123

Gnomad4 OTH AF: 0.118

Alfa AF: 0.129 Hom.: 1066

Bravo AF: 0.109

TwinsUK AF: 0.119 AC: 441

ALSPAC AF: 0.125 AC: 481

ESP6500AA AF: 0.0785 AC: 346

ESP6500EA AF: 0.129 AC: 1106

ExAC AF: 0.113 AC: 13722

Asia WGS AF: 0.107 AC: 371 AN: 3478

EpiCase AF: 0.130

EpiControl AF: 0.134

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

CHARGE syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 09, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	16
Dann	Benign	0.91
DEOGEN2	Benign	0.027	T;T;.;.
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.54	D
MetaRNN	Benign	0.0017	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.0	N;N;.;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.060	N;.;N;.
REVEL	Benign	0.049
Sift	Benign	0.54	T;.;T;.
Sift4G	Benign	0.45	T;.;T;.
Polyphen		0.0	B;B;.;.
Vest4		0.22
MPC		0.64
ClinPred		0.014	T
GERP RS		1.9
Varity_R		0.24
gMVP		0.64

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: rs61729612; hg19: chr7-83037731; COSMIC: COSV57100584;