rs17275986

Variant names:

• chr7-80789373-A-G
• rs17275986
• NM_006379.5:c.1287T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_006379.5(SEMA3C):​c.1287T>C​(p.Tyr429Tyr) 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 (no stars).

• Frequency:
  • Genomes: 𝑓 0.15 (2073 hom., cov: 32)
  • Exomes 𝑓: 0.19 (27142 hom.)
• Consequence: SEMA3C NM_006379.5 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.45
• Publications: 15 publications found

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

Our verdict: Benign. The variant received -14 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 VariationId is 3060714.Status of the report is no_assertion_criteria_provided, 0 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 rank	MANE	Protein	UniProt
SEMA3C	NM_006379.5	c.1287T>C	p.Tyr429Tyr	synonymous_variant	Exon 12 of 18	ENST00000265361.8	NP_006370.1
SEMA3C	NM_001350120.2	c.1341T>C	p.Tyr447Tyr	synonymous_variant	Exon 12 of 18		NP_001337049.1
SEMA3C	NM_001350121.2	c.1113T>C	p.Tyr371Tyr	synonymous_variant	Exon 13 of 19		NP_001337050.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEMA3C	ENST00000265361.8	c.1287T>C	p.Tyr429Tyr	synonymous_variant	Exon 12 of 18	1	NM_006379.5	ENSP00000265361.3
SEMA3C	ENST00000419255.6	c.1287T>C	p.Tyr429Tyr	synonymous_variant	Exon 12 of 18	2		ENSP00000411193.2

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

GnomAD2 exomes AF: 0.157 AC: 39483 AN: 251276 AF XY: 0.160

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 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

African (AFR) AF: 0.0725 AC: 2426 AN: 33472

American (AMR) AF: 0.108 AC: 4829 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 2847 AN: 26122

East Asian (EAS) AF: 0.0751 AC: 2979 AN: 39682

South Asian (SAS) AF: 0.115 AC: 9955 AN: 86242

European-Finnish (FIN) AF: 0.204 AC: 10887 AN: 53410

Middle Eastern (MID) AF: 0.0793 AC: 457 AN: 5766

European-Non Finnish (NFE) AF: 0.207 AC: 229793 AN: 1111760

Other (OTH) AF: 0.166 AC: 10045 AN: 60388

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

African (AFR) AF: 0.0805 AC: 3340 AN: 41500

American (AMR) AF: 0.140 AC: 2145 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 352 AN: 3466

East Asian (EAS) AF: 0.0899 AC: 465 AN: 5172

South Asian (SAS) AF: 0.119 AC: 574 AN: 4814

European-Finnish (FIN) AF: 0.206 AC: 2178 AN: 10584

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.203 AC: 13814 AN: 67994

Other (OTH) AF: 0.133 AC: 281 AN: 2110

Alfa AF: 0.181 Hom.: 13002

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: no assertion criteria provided

Submissions by phenotype

SEMA3C-related disorder Benign:1

Aug 19, 2022

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
PhyloP100		1.5
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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