rs1527482

Positions:

chr7-80798214-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP3BP4_StrongBP6_Very_StrongBA1

The NM_006379.5(SEMA3C):c.1009G>A(p.Val337Met) variant causes a missense change. The variant allele was found at a frequency of 0.0126 in 1,488,400 control chromosomes in the GnomAD database, including 591 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.014 ( 63 hom., cov: 32)

Exomes 𝑓: 0.012 ( 528 hom. )

Consequence

SEMA3C
NM_006379.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 6.16

Variant links:

Genes affected

SEMA3C (HGNC:10725): (semaphorin 3C) This gene encodes a secreted glycoprotein that belongs to the semaphorin class 3 family of neuronal guidance cues. The encoded protein contains an N-terminal sema domain, integrin and immunoglobulin-like domains, and a C-terminal basic domain. Homodimerization and proteolytic cleavage of the C-terminal propeptide are necessary for the function of the encoded protein. It binds a neuropilin co-receptor before forming a heterotrimeric complex with an associated plexin. An increase in the expression of this gene correlates with an increase in cancer cell invasion and adhesion. Naturally occurring mutations in this gene are associated with Hirschsprung disease. [provided by RefSeq, May 2017]

SEMA3C links:

SEMA3C (HGNC:):

SEMA3C links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 6: AlphaMissense, Cadd, Eigen, FATHMM_MKL, MutationAssessor, PrimateAI [when BayesDel_addAF, max_spliceai, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.005048603).

BP6

Variant 7-80798214-C-T is Benign according to our data. Variant chr7-80798214-C-T is described in ClinVar as [Benign]. Clinvar id is 1272490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0647 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SEMA3C	NM_006379.5 linkuse as main transcript	c.1009G>A	p.Val337Met	missense_variant	11/18	ENST00000265361.8	NP_006370.1	Q99985-1
SEMA3C	NM_001350120.2 linkuse as main transcript	c.1063G>A	p.Val355Met	missense_variant	11/18		NP_001337049.1
SEMA3C	NM_001350121.2 linkuse as main transcript	c.835G>A	p.Val279Met	missense_variant	12/19		NP_001337050.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SEMA3C	ENST00000265361.8 linkuse as main transcript	c.1009G>A	p.Val337Met	missense_variant	11/18	1	NM_006379.5	ENSP00000265361.3		Q99985-1

Frequencies

GnomAD3 genomes

AF:

0.0144

AC:

2185

AN:

151890

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00285

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0677

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.0602

Gnomad SAS

AF:

0.0382

Gnomad FIN

AF:

0.000949

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00715

Gnomad OTH

AF:

0.0191

GnomAD3 exomes

AF:

0.0284

AC:

4958

AN:

174880

Hom.:

301

AF XY:

0.0249

AC XY:

2408

AN XY:

96522

show subpopulations

Gnomad AFR exome

AF:

0.00310

Gnomad AMR exome

AF:

0.175

Gnomad ASJ exome

AF:

0.00170

Gnomad EAS exome

AF:

0.0711

Gnomad SAS exome

AF:

0.0364

Gnomad FIN exome

AF:

0.000701

Gnomad NFE exome

AF:

0.00639

Gnomad OTH exome

AF:

0.0254

GnomAD4 exome

AF:

0.0124

AC:

16509

AN:

1336392

Hom.:

528

Cov.:

AF XY:

0.0126

AC XY:

8305

AN XY:

658144

show subpopulations

Gnomad4 AFR exome

AF:

0.00146

Gnomad4 AMR exome

AF:

0.149

Gnomad4 ASJ exome

AF:

0.00114

Gnomad4 EAS exome

AF:

0.0746

Gnomad4 SAS exome

AF:

0.0378

Gnomad4 FIN exome

AF:

0.00126

Gnomad4 NFE exome

AF:

0.00647

Gnomad4 OTH exome

AF:

0.0139

GnomAD4 genome

AF:

0.0145

AC:

2197

AN:

152008

Hom.:

Cov.:

AF XY:

0.0158

AC XY:

1173

AN XY:

74300

show subpopulations

Gnomad4 AFR

AF:

0.00285

Gnomad4 AMR

AF:

0.0681

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.0610

Gnomad4 SAS

AF:

0.0384

Gnomad4 FIN

AF:

0.000949

Gnomad4 NFE

AF:

0.00715

Gnomad4 OTH

AF:

0.0189

Alfa

AF:

0.0115

Hom.:

Bravo

AF:

0.0192

TwinsUK

AF:

0.00620

AC:

ALSPAC

AF:

0.00752

AC:

ESP6500AA

AF:

0.00522

AC:

ESP6500EA

AF:

0.00488

AC:

ExAC

AF:

0.0264

AC:

3208

Asia WGS

AF:

0.0530

AC:

185

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 05, 2020	This variant is associated with the following publications: (PMID: 25839327, 21898659, 31240788) -

SEMA3C-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 24, 2022

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.46

T;T

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

.;D

MetaRNN

Benign

0.0050

T;T

MetaSVM

Benign

-0.59

MutationAssessor

Pathogenic

4.0

H;H

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-2.8

D;D

REVEL

Uncertain

0.35

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;D

Vest4

0.77

MPC

0.58

ClinPred

0.089

GERP RS

5.7

Varity_R

0.90

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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