rs12401573

Positions:

chr1-156176427-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_022367.4(SEMA4A):c.1716C>T(p.Pro572=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.564 in 1,612,844 control chromosomes in the GnomAD database, including 261,818 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.52 ( 21192 hom., cov: 31)

Exomes 𝑓: 0.57 ( 240626 hom. )

Consequence

SEMA4A
NM_022367.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.946

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BP6

Variant 1-156176427-C-T is Benign according to our data. Variant chr1-156176427-C-T is described in ClinVar as [Benign]. Clinvar id is 261576.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156176427-C-T is described in Lovd as [Benign]. Variant chr1-156176427-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=0.946 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.594 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SEMA4A	NM_022367.4 linkuse as main transcript	c.1716C>T	p.Pro572=	synonymous_variant	15/15	ENST00000368285.8	NP_071762.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SEMA4A	ENST00000368285.8 linkuse as main transcript	c.1716C>T	p.Pro572=	synonymous_variant	15/15	1	NM_022367.4	ENSP00000357268	P1	Q9H3S1-1

Frequencies

GnomAD3 genomes

AF:

0.518

AC:

78704

AN:

151876

Hom.:

21173

Cov.:

show subpopulations

Gnomad AFR

AF:

0.405

Gnomad AMI

AF:

0.435

Gnomad AMR

AF:

0.542

Gnomad ASJ

AF:

0.549

Gnomad EAS

AF:

0.251

Gnomad SAS

AF:

0.464

Gnomad FIN

AF:

0.556

Gnomad MID

AF:

0.570

Gnomad NFE

AF:

0.599

Gnomad OTH

AF:

0.539

GnomAD3 exomes

AF:

0.527

AC:

132332

AN:

250978

Hom.:

36221

AF XY:

0.529

AC XY:

71806

AN XY:

135680

show subpopulations

Gnomad AFR exome

AF:

0.402

Gnomad AMR exome

AF:

0.532

Gnomad ASJ exome

AF:

0.547

Gnomad EAS exome

AF:

0.240

Gnomad SAS exome

AF:

0.473

Gnomad FIN exome

AF:

0.562

Gnomad NFE exome

AF:

0.595

Gnomad OTH exome

AF:

0.558

GnomAD4 exome

AF:

0.569

AC:

831127

AN:

1460850

Hom.:

240626

Cov.:

AF XY:

0.566

AC XY:

411341

AN XY:

726826

show subpopulations

Gnomad4 AFR exome

AF:

0.408

Gnomad4 AMR exome

AF:

0.534

Gnomad4 ASJ exome

AF:

0.546

Gnomad4 EAS exome

AF:

0.247

Gnomad4 SAS exome

AF:

0.475

Gnomad4 FIN exome

AF:

0.564

Gnomad4 NFE exome

AF:

0.596

Gnomad4 OTH exome

AF:

0.550

GnomAD4 genome

AF:

0.518

AC:

78757

AN:

151994

Hom.:

21192

Cov.:

AF XY:

0.515

AC XY:

38224

AN XY:

74290

show subpopulations

Gnomad4 AFR

AF:

0.405

Gnomad4 AMR

AF:

0.542

Gnomad4 ASJ

AF:

0.549

Gnomad4 EAS

AF:

0.251

Gnomad4 SAS

AF:

0.464

Gnomad4 FIN

AF:

0.556

Gnomad4 NFE

AF:

0.599

Gnomad4 OTH

AF:

0.542

Alfa

AF:

0.579

Hom.:

40397

Bravo

AF:

0.513

Asia WGS

AF:

0.393

AC:

1371

AN:

3478

EpiCase

AF:

0.585

EpiControl

AF:

0.587

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 14, 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. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Cone-rod dystrophy 10

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Retinitis pigmentosa 35

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

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

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Benign

0.35

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