rs1527482

chr7-80798214-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP3 BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.16

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]

ACMG classification

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	UniProt
SEMA3C	NM_006379.5	c.1009G>A	p.Val337Met	missense_variant	11/18	ENST00000265361.8
SEMA3C	NM_001350120.2	c.1063G>A	p.Val355Met	missense_variant	11/18
SEMA3C	NM_001350121.2	c.835G>A	p.Val279Met	missense_variant	12/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEMA3C	ENST00000265361.8	c.1009G>A	p.Val337Met	missense_variant	11/18	1	NM_006379.5	P1
SEMA3C	ENST00000419255.6	c.1009G>A	p.Val337Met	missense_variant	11/18	2		P1
SEMA3C	ENST00000475955.1	n.25G>A		non_coding_transcript_exon_variant	1/2	4
SEMA3C	ENST00000458729.5	c.*542G>A		3_prime_UTR_variant, NMD_transcript_variant	8/9	2

Frequencies

GnomAD3 genomes AF: 0.0144 AC: 2185 AN: 151890 Hom.: 63 Cov.: 32

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

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.: 31 AF XY: 0.0126 AC XY: 8305 AN XY: 658144

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.: 63 Cov.: 32 AF XY: 0.0158 AC XY: 1173 AN XY: 74300

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.: 97

Bravo AF: 0.0192

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.00752 AC: 29

ESP6500AA AF: 0.00522 AC: 23

ESP6500EA AF: 0.00488 AC: 42

ExAC AF: 0.0264 AC: 3208

Asia WGS AF: 0.0530 AC: 185 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

SEMA3C-related disorder Benign:1

Benign, criteria provided, single submitter

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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 05, 2020

This variant is associated with the following publications: (PMID: 25839327, 21898659, 31240788) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Uncertain	0.040
Cadd	Pathogenic	32
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.98	D
MetaRNN	Benign	0.0050	T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Pathogenic	4.0	H;H
MutationTaster	Benign	4.2e-8	P;P;P;P
PrimateAI	Pathogenic	0.80	T
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	T
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

Other links and lift over

dbSNP: rs1527482; hg19: chr7-80427530; COSMIC: COSV54853624;