rs41265017

chr1-156176849-G-A

Variant summary

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

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. 12/19 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:13
• Conservation: PhyloP100: 2.13

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 -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/exons	MANE	UniProt
SEMA4A	NM_022367.4	c.2138G>A	p.Arg713Gln	missense_variant	15/15	ENST00000368285.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEMA4A	ENST00000368285.8	c.2138G>A	p.Arg713Gln	missense_variant	15/15	1	NM_022367.4	P1
SEMA4A	ENST00000355014.6	c.2138G>A	p.Arg713Gln	missense_variant	15/15	1		P1
SEMA4A	ENST00000368282.1	c.2138G>A	p.Arg713Gln	missense_variant	14/14	1		P1
SEMA4A	ENST00000368284.5	c.1742G>A	p.Arg581Gln	missense_variant	13/13	2

Frequencies

GnomAD3 genomes AF: 0.0326 AC: 4955 AN: 152214 Hom.: 132 Cov.: 32

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

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.: 34 AF XY: 0.0417 AC XY: 30353 AN XY: 727242

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.: 32 AF XY: 0.0325 AC XY: 2422 AN XY: 74498

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: 40

ESP6500EA AF: 0.0478 AC: 411

ExAC AF: 0.0354 AC: 4297

Asia WGS AF: 0.0150 AC: 53 AN: 3478

EpiCase AF: 0.0582

EpiControl AF: 0.0551

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 25, 2016	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% -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 03, 2014	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 25, 2018	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. -

Retinitis pigmentosa 35 Uncertain:1 Benign:1

Uncertain significance, no assertion criteria provided	literature only	OMIM	Jan 01, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

Cone-rod dystrophy 10 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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, Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Retinitis pigmentosa Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.34
Cadd	Uncertain	24
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	D
MetaRNN	Benign	0.0022	T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	2.0	M;M;.;.;M
MutationTaster	Benign	0.15	P;P;P;P;P;P
PrimateAI	Benign	0.43	T
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	T
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

Other links and lift over

dbSNP: rs41265017; hg19: chr1-156146640; COSMIC: COSV61772569; COSMIC: COSV61772569;