rs12401573

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_022367.4(SEMA4A):c.1716C>T(p.Pro572Pro) 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

Publications

28 publications found

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 Gene-Disease associations (from GenCC):

cone-rod dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial colorectal cancer type X
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
retinitis pigmentosa 35
Inheritance: AR, Unknown Classification: LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
cone-rod dystrophy 10
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
Lynch syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

SEMA4A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 261576.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
SEMA4A	NM_022367.4 link	c.1716C>T	p.Pro572Pro	synonymous_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.1716C>T	p.Pro572Pro	synonymous_variant	Exon 15 of 15	1	NM_022367.4	ENSP00000357268.3		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

GnomAD2 exomes

AF:

0.527

AC:

132332

AN:

250978

AF XY:

0.529

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 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

African (AFR)

AF:

0.408

AC:

13634

AN:

33456

American (AMR)

AF:

0.534

AC:

23863

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.546

AC:

14276

AN:

26128

East Asian (EAS)

AF:

0.247

AC:

9819

AN:

39690

South Asian (SAS)

AF:

0.475

AC:

40987

AN:

86240

European-Finnish (FIN)

AF:

0.564

AC:

30118

AN:

53410

Middle Eastern (MID)

AF:

0.605

AC:

3490

AN:

5766

European-Non Finnish (NFE)

AF:

0.596

AC:

661747

AN:

1111112

Other (OTH)

AF:

0.550

AC:

33193

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

17951

35902

53852

71803

89754

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17822

35644

53466

71288

89110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.518

AC:

78757

AN:

151994

Hom.:

21192

Cov.:

AF XY:

0.515

AC XY:

38224

AN XY:

74290

show subpopulations

African (AFR)

AF:

0.405

AC:

16780

AN:

41436

American (AMR)

AF:

0.542

AC:

8276

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.549

AC:

1904

AN:

3468

East Asian (EAS)

AF:

0.251

AC:

1296

AN:

5162

South Asian (SAS)

AF:

0.464

AC:

2235

AN:

4816

European-Finnish (FIN)

AF:

0.556

AC:

5874

AN:

10564

Middle Eastern (MID)

AF:

0.561

AC:

165

AN:

294

European-Non Finnish (NFE)

AF:

0.599

AC:

40684

AN:

67948

Other (OTH)

AF:

0.542

AC:

1146

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1902

3804

5705

7607

9509

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

694

1388

2082

2776

3470

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.571

Hom.:

56374

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

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 14, 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. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Cone-rod dystrophy 10

Benign:2

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinitis pigmentosa 35

Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinal dystrophy

Benign:1

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Retinitis pigmentosa

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.35

PhyloP100

0.95

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over