rs17275986

Positions:

• chr7-80789373-A-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_006379.5(SEMA3C):​c.1287T>C​(p.Tyr429=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.184 in 1,613,682 control chromosomes in the GnomAD database, including 29,215 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.15 (2073 hom., cov: 32)
  • Exomes 𝑓: 0.19 (27142 hom.)
• Consequence: SEMA3C NM_006379.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.45

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 7-80789373-A-G is Benign according to our data. Variant chr7-80789373-A-G is described in ClinVar as [Benign]. Clinvar id is 3060714.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.45 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.2 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEMA3C	NM_006379.5	c.1287T>C	p.Tyr429=	synonymous_variant	12/18	ENST00000265361.8
SEMA3C	NM_001350120.2	c.1341T>C	p.Tyr447=	synonymous_variant	12/18
SEMA3C	NM_001350121.2	c.1113T>C	p.Tyr371=	synonymous_variant	13/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEMA3C	ENST00000265361.8	c.1287T>C	p.Tyr429=	synonymous_variant	12/18	1	NM_006379.5	P1
SEMA3C	ENST00000419255.6	c.1287T>C	p.Tyr429=	synonymous_variant	12/18	2		P1

Frequencies

GnomAD3 genomes AF: 0.154 AC: 23355 AN: 152012 Hom.: 2072 Cov.: 32

Gnomad AFR AF: 0.0806

Gnomad AMI AF: 0.195

Gnomad AMR AF: 0.141

Gnomad ASJ AF: 0.102

Gnomad EAS AF: 0.0897

Gnomad SAS AF: 0.120

Gnomad FIN AF: 0.206

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.203

Gnomad OTH AF: 0.132

GnomAD3 exomes AF: 0.157 AC: 39483 AN: 251276 Hom.: 3534 AF XY: 0.160 AC XY: 21687 AN XY: 135798

Gnomad AFR exome AF: 0.0773

Gnomad AMR exome AF: 0.105

Gnomad ASJ exome AF: 0.110

Gnomad EAS exome AF: 0.0911

Gnomad SAS exome AF: 0.113

Gnomad FIN exome AF: 0.203

Gnomad NFE exome AF: 0.203

Gnomad OTH exome AF: 0.151

GnomAD4 exome AF: 0.188 AC: 274218 AN: 1461552 Hom.: 27142 Cov.: 32 AF XY: 0.186 AC XY: 135062 AN XY: 727088

Gnomad4 AFR exome AF: 0.0725

Gnomad4 AMR exome AF: 0.108

Gnomad4 ASJ exome AF: 0.109

Gnomad4 EAS exome AF: 0.0751

Gnomad4 SAS exome AF: 0.115

Gnomad4 FIN exome AF: 0.204

Gnomad4 NFE exome AF: 0.207

Gnomad4 OTH exome AF: 0.166

GnomAD4 genome AF: 0.154 AC: 23355 AN: 152130 Hom.: 2073 Cov.: 32 AF XY: 0.154 AC XY: 11441 AN XY: 74340

Gnomad4 AFR AF: 0.0805

Gnomad4 AMR AF: 0.140

Gnomad4 ASJ AF: 0.102

Gnomad4 EAS AF: 0.0899

Gnomad4 SAS AF: 0.119

Gnomad4 FIN AF: 0.206

Gnomad4 NFE AF: 0.203

Gnomad4 OTH AF: 0.133

Alfa AF: 0.181 Hom.: 6530

Bravo AF: 0.141

Asia WGS AF: 0.112 AC: 388 AN: 3478

EpiCase AF: 0.190

EpiControl AF: 0.185

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

SEMA3C-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 19, 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
BayesDel_noAF	Benign	-0.56
CADD	Benign	7.1
DANN	Benign	0.38

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

Other links and lift over

dbSNP: rs17275986; hg19: chr7-80418689; COSMIC: COSV54848087; COSMIC: COSV54848087;