7-80745029-T-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_006379.5(SEMA3C):c.2121A>G(p.Gln707=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00199 in 1,614,064 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (0 hom.)
• Consequence: SEMA3C NM_006379.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.540

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 -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 7-80745029-T-C is Benign according to our data. Variant chr7-80745029-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 783002.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.54 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEMA3C	NM_006379.5	c.2121A>G	p.Gln707=	synonymous_variant	18/18	ENST00000265361.8
SEMA3C	NM_001350120.2	c.2175A>G	p.Gln725=	synonymous_variant	18/18
SEMA3C	NM_001350121.2	c.1947A>G	p.Gln649=	synonymous_variant	19/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEMA3C	ENST00000265361.8	c.2121A>G	p.Gln707=	synonymous_variant	18/18	1	NM_006379.5	P1
SEMA3C	ENST00000419255.6	c.2121A>G	p.Gln707=	synonymous_variant	18/18	2		P1

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 153 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00179

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000816 AC: 205 AN: 251160 Hom.: 0 AF XY: 0.000811 AC XY: 110 AN XY: 135710

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00155

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.00210 AC: 3063 AN: 1461746 Hom.: 0 Cov.: 69 AF XY: 0.00203 AC XY: 1474 AN XY: 727180

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.00261

Gnomad4 OTH exome AF: 0.00212

GnomAD4 genome AF: 0.00100 AC: 153 AN: 152318 Hom.: 0 Cov.: 33 AF XY: 0.000765 AC XY: 57 AN XY: 74484

Gnomad4 AFR AF: 0.000601

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00179

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00143 Hom.: 0

Bravo AF: 0.000929

EpiCase AF: 0.00136

EpiControl AF: 0.00130

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

SEMA3C-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 21, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	4.9
Dann	Benign	0.29

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: rs149650168; hg19: chr7-80374345;