7-80748909-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_006379.5(SEMA3C):c.1831A>G(p.Arg611Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000054 in 1,611,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000056 ( 0 hom. )

Consequence

SEMA3C
NM_006379.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.626

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3940729).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SEMA3C	NM_006379.5 linkuse as main transcript	c.1831A>G	p.Arg611Gly	missense_variant	17/18	ENST00000265361.8
SEMA3C	NM_001350120.2 linkuse as main transcript	c.1885A>G	p.Arg629Gly	missense_variant	17/18
SEMA3C	NM_001350121.2 linkuse as main transcript	c.1657A>G	p.Arg553Gly	missense_variant	18/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEMA3C	ENST00000265361.8 linkuse as main transcript	c.1831A>G	p.Arg611Gly	missense_variant	17/18	1	NM_006379.5	P1	Q99985-1
SEMA3C	ENST00000419255.6 linkuse as main transcript	c.1831A>G	p.Arg611Gly	missense_variant	17/18	2		P1	Q99985-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000132

AC:

AN:

249058

Hom.:

AF XY:

0.000134

AC XY:

AN XY:

134688

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000587

Gnomad ASJ exome

AF:

0.00232

Gnomad EAS exome

AF:

0.0000547

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000443

Gnomad OTH exome

AF:

0.000330

GnomAD4 exome

AF:

0.0000555

AC:

AN:

1459370

Hom.:

Cov.:

AF XY:

0.0000592

AC XY:

AN XY:

726046

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000452

Gnomad4 ASJ exome

AF:

0.00208

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000248

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000576

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 27, 2022

The c.1831A>G (p.R611G) alteration is located in exon 17 (coding exon 16) of the SEMA3C gene. This alteration results from a A to G substitution at nucleotide position 1831, causing the arginine (R) at amino acid position 611 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

0.090

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.46

T;T

Eigen

Benign

0.15

Eigen_PC

Benign

0.11

FATHMM_MKL

Benign

0.75

M_CAP

Benign

0.069

MetaRNN

Benign

0.39

T;T

MetaSVM

Benign

-0.63

MutationAssessor

Benign

1.8

L;L

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-3.2

D;D

REVEL

Uncertain

0.43

Sift

Benign

0.056

T;T

Sift4G

Benign

0.14

T;T

Polyphen

1.0

D;D

Vest4

0.79

MVP

0.65

MPC

0.71

ClinPred

0.27

GERP RS

1.4

Varity_R

0.76

gMVP

0.67

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