7-80749003-G-C

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.1737C>G(p.Val579=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.97 in 1,611,996 control chromosomes in the GnomAD database, including 761,424 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.91 (64175 hom., cov: 31)
  • Exomes 𝑓: 0.98 (697249 hom.)
• Consequence: SEMA3C NM_006379.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.413

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 7-80749003-G-C is Benign according to our data. Variant chr7-80749003-G-C is described in ClinVar as [Benign]. Clinvar id is 3060860.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.413 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.987 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEMA3C	NM_006379.5	c.1737C>G	p.Val579=	synonymous_variant	17/18	ENST00000265361.8
SEMA3C	NM_001350120.2	c.1791C>G	p.Val597=	synonymous_variant	17/18
SEMA3C	NM_001350121.2	c.1563C>G	p.Val521=	synonymous_variant	18/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEMA3C	ENST00000265361.8	c.1737C>G	p.Val579=	synonymous_variant	17/18	1	NM_006379.5	P1
SEMA3C	ENST00000419255.6	c.1737C>G	p.Val579=	synonymous_variant	17/18	2		P1

Frequencies

GnomAD3 genomes AF: 0.913 AC: 138705 AN: 152004 Hom.: 64165 Cov.: 31

Gnomad AFR AF: 0.760

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.936

Gnomad ASJ AF: 0.975

Gnomad EAS AF: 0.763

Gnomad SAS AF: 0.939

Gnomad FIN AF: 0.983

Gnomad MID AF: 0.968

Gnomad NFE AF: 0.993

Gnomad OTH AF: 0.938

GnomAD3 exomes AF: 0.942 AC: 234834 AN: 249162 Hom.: 111450 AF XY: 0.949 AC XY: 127740 AN XY: 134616

Gnomad AFR exome AF: 0.760

Gnomad AMR exome AF: 0.912

Gnomad ASJ exome AF: 0.978

Gnomad EAS exome AF: 0.764

Gnomad SAS exome AF: 0.953

Gnomad FIN exome AF: 0.983

Gnomad NFE exome AF: 0.992

Gnomad OTH exome AF: 0.962

GnomAD4 exome AF: 0.976 AC: 1424727 AN: 1459874 Hom.: 697249 Cov.: 38 AF XY: 0.976 AC XY: 708842 AN XY: 726230

Gnomad4 AFR exome AF: 0.752

Gnomad4 AMR exome AF: 0.913

Gnomad4 ASJ exome AF: 0.977

Gnomad4 EAS exome AF: 0.799

Gnomad4 SAS exome AF: 0.953

Gnomad4 FIN exome AF: 0.984

Gnomad4 NFE exome AF: 0.994

Gnomad4 OTH exome AF: 0.955

GnomAD4 genome AF: 0.912 AC: 138766 AN: 152122 Hom.: 64175 Cov.: 31 AF XY: 0.912 AC XY: 67840 AN XY: 74366

Gnomad4 AFR AF: 0.759

Gnomad4 AMR AF: 0.935

Gnomad4 ASJ AF: 0.975

Gnomad4 EAS AF: 0.762

Gnomad4 SAS AF: 0.939

Gnomad4 FIN AF: 0.983

Gnomad4 NFE AF: 0.993

Gnomad4 OTH AF: 0.939

Alfa AF: 0.971 Hom.: 22790

Bravo AF: 0.902

Asia WGS AF: 0.855 AC: 2975 AN: 3478

EpiCase AF: 0.991

EpiControl AF: 0.991

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

Jul 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	5.7
Dann	Benign	0.74

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: rs2272351; hg19: chr7-80378319;