rs41265017

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_022367.4(SEMA4A):c.2138G>A(p.Arg713Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0399 in 1,614,210 control chromosomes in the GnomAD database, including 1,578 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.033 ( 132 hom., cov: 32)

Exomes 𝑓: 0.041 ( 1446 hom. )

Consequence

SEMA4A
NM_022367.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:16

Conservation

PhyloP100: 2.13

Variant links:

Genes affected

SEMA4A (HGNC:10729): (semaphorin 4A) This gene encodes a member of the semaphorin family of soluble and transmembrane proteins. Semaphorins are involved in numerous functions, including axon guidance, morphogenesis, carcinogenesis, and immunomodulation. The encoded protein is a single-pass type I membrane protein containing an immunoglobulin-like C2-type domain, a PSI domain and a sema domain. It inhibits axonal extension by providing local signals to specify territories inaccessible for growing axons. It is an activator of T-cell-mediated immunity and suppresses vascular endothelial growth factor (VEGF)-mediated endothelial cell migration and proliferation in vitro and angiogenesis in vivo. Mutations in this gene are associated with retinal degenerative diseases including retinitis pigmentosa type 35 (RP35) and cone-rod dystrophy type 10 (CORD10). Multiple alternatively spliced transcript variants encoding different isoforms have been identified.[provided by RefSeq, Sep 2010]

SEMA4A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0022318065).

BP6

Variant 1-156176849-G-A is Benign according to our data. Variant chr1-156176849-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156176849-G-A is described in Lovd as [Benign]. Variant chr1-156176849-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-156176849-G-A is described in Lovd as [Likely_benign].

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0827 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA4A	NM_022367.4 link	c.2138G>A	p.Arg713Gln	missense_variant	Exon 15 of 15	ENST00000368285.8	NP_071762.2	Q9H3S1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEMA4A	ENST00000368285.8 link	c.2138G>A	p.Arg713Gln	missense_variant	Exon 15 of 15	1	NM_022367.4	ENSP00000357268.3		Q9H3S1-1

Frequencies

GnomAD3 genomes

AF:

0.0326

AC:

4955

AN:

152214

Hom.:

132

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00743

Gnomad AMI

AF:

0.0241

Gnomad AMR

AF:

0.0385

Gnomad ASJ

AF:

0.103

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.0376

Gnomad FIN

AF:

0.0291

Gnomad MID

AF:

0.133

Gnomad NFE

AF:

0.0447

Gnomad OTH

AF:

0.0478

GnomAD3 exomes

AF:

0.0374

AC:

9405

AN:

251410

Hom.:

279

AF XY:

0.0399

AC XY:

5424

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.00671

Gnomad AMR exome

AF:

0.0309

Gnomad ASJ exome

AF:

0.0958

Gnomad EAS exome

AF:

0.000326

Gnomad SAS exome

AF:

0.0404

Gnomad FIN exome

AF:

0.0296

Gnomad NFE exome

AF:

0.0446

Gnomad OTH exome

AF:

0.0506

GnomAD4 exome

AF:

0.0407

AC:

59460

AN:

1461878

Hom.:

1446

Cov.:

AF XY:

0.0417

AC XY:

30353

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00747

Gnomad4 AMR exome

AF:

0.0317

Gnomad4 ASJ exome

AF:

0.0972

Gnomad4 EAS exome

AF:

0.000302

Gnomad4 SAS exome

AF:

0.0426

Gnomad4 FIN exome

AF:

0.0278

Gnomad4 NFE exome

AF:

0.0421

Gnomad4 OTH exome

AF:

0.0459

GnomAD4 genome

AF:

0.0325

AC:

4956

AN:

152332

Hom.:

132

Cov.:

AF XY:

0.0325

AC XY:

2422

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.00743

Gnomad4 AMR

AF:

0.0384

Gnomad4 ASJ

AF:

0.103

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.0381

Gnomad4 FIN

AF:

0.0291

Gnomad4 NFE

AF:

0.0447

Gnomad4 OTH

AF:

0.0473

Alfa

AF:

0.0464

Hom.:

297

Bravo

AF:

0.0319

TwinsUK

AF:

0.0348

AC:

129

ALSPAC

AF:

0.0384

AC:

148

ESP6500AA

AF:

0.00908

AC:

ESP6500EA

AF:

0.0478

AC:

411

ExAC

AF:

0.0354

AC:

4297

Asia WGS

AF:

0.0150

AC:

AN:

3478

EpiCase

AF:

0.0582

EpiControl

AF:

0.0551

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 25, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 451/13006=3.4% -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 03, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:4

May 25, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cone-rod dystrophy 10

Benign:3

Apr 11, 2023

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 17, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as likely benign. Following criteria are met: 0308 - Population frequency for this variant is out of keeping with known incidence of cone-rod dystrophy 10 (MIM#610283), with 132 homozygotes in gnomAD v3. (SB) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Retinitis pigmentosa 35

Uncertain:1Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2013

OMIM

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Retinitis Pigmentosa, Recessive

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinal dystrophy

Benign:1

Jan 01, 2020

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.049

T;T;.;T;T

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.064

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.83

.;.;T;T;T

MetaRNN

Benign

0.0022

T;T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

2.0

M;M;.;.;M

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.37

N;N;N;.;N

REVEL

Benign

0.24

Sift

Benign

0.30

T;T;T;.;T

Sift4G

Benign

0.39

T;T;T;T;T

Polyphen

0.23

B;B;.;.;B

Vest4

0.068

MPC

0.21

ClinPred

0.0064

GERP RS

4.2

Varity_R

0.059

gMVP

0.32

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over