rs2075164

chr1-156175180-G-Achr1-156175180-G-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM5 BP4_Strong BP6_Very_Strong BA1

The NM_022367.4(SEMA4A):c.1529G>A(p.Arg510Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00243 in 1,614,066 control chromosomes in the GnomAD database, including 128 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R510W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0025 (14 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (114 hom.)
• Consequence: SEMA4A NM_022367.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.76

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-156175179-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 384117.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.008191496).
• BP6: Variant 1-156175180-G-A is Benign according to our data. Variant chr1-156175180-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 194261.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156175180-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0557 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEMA4A	NM_022367.4	c.1529G>A	p.Arg510Gln	missense_variant	13/15	ENST00000368285.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEMA4A	ENST00000368285.8	c.1529G>A	p.Arg510Gln	missense_variant	13/15	1	NM_022367.4	P1

Frequencies

GnomAD3 genomes AF: 0.00254 AC: 387 AN: 152122 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.0609

Gnomad SAS AF: 0.00394

Gnomad FIN AF: 0.00189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00584 AC: 1468 AN: 251342 Hom.: 41 AF XY: 0.00557 AC XY: 757 AN XY: 135848

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00248

Gnomad EAS exome AF: 0.0687

Gnomad SAS exome AF: 0.00307

Gnomad FIN exome AF: 0.00194

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00242 AC: 3531 AN: 1461826 Hom.: 114 Cov.: 33 AF XY: 0.00244 AC XY: 1772 AN XY: 727224

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00329

Gnomad4 EAS exome AF: 0.0700

Gnomad4 SAS exome AF: 0.00345

Gnomad4 FIN exome AF: 0.00156

Gnomad4 NFE exome AF: 0.000106

Gnomad4 OTH exome AF: 0.00252

GnomAD4 genome AF: 0.00255 AC: 388 AN: 152240 Hom.: 14 Cov.: 32 AF XY: 0.00320 AC XY: 238 AN XY: 74424

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.0612

Gnomad4 SAS AF: 0.00394

Gnomad4 FIN AF: 0.00189

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00334 Hom.: 31

Bravo AF: 0.00308

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00572 AC: 695

Asia WGS AF: 0.0230 AC: 81 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 25, 2015	- -
Benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Benign - Stand Alone. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. -

Cone-rod dystrophy 10 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Retinitis Pigmentosa, Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Retinitis pigmentosa 35 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 20, 2024

- -

Retinal dystrophy Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Retinitis pigmentosa Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	22
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.26	T;T;.;T;T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.87	D
MetaRNN	Benign	0.0082	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;M;.;.;M
MutationTaster	Benign	0.99	D;D;D;D;D;D
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.5	D;D;D;.;D
REVEL	Benign	0.12
Sift	Benign	0.039	D;D;D;.;D
Sift4G	Benign	0.077	T;T;T;T;T
Polyphen		0.78	P;P;.;.;P
Vest4		0.23
MVP		0.20
MPC		0.45
ClinPred		0.043	T
GERP RS		3.7
Varity_R		0.55
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2075164; hg19: chr1-156144971; COSMIC: COSV61772592; COSMIC: COSV61772592;