7-80745026-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.2124T>C(p.Tyr708=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.98 in 1,614,054 control chromosomes in the GnomAD database, including 777,793 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.93 (66717 hom., cov: 32)
  • Exomes 𝑓: 0.99 (711076 hom.)
• Consequence: SEMA3C NM_006379.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.77

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=-0.61).
• BP6: Variant 7-80745026-A-G is Benign according to our data. Variant chr7-80745026-A-G is described in ClinVar as [Benign]. Clinvar id is 3060435.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=2.77 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) 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.2124T>C	p.Tyr708=	synonymous_variant	18/18	ENST00000265361.8
SEMA3C	NM_001350120.2	c.2178T>C	p.Tyr726=	synonymous_variant	18/18
SEMA3C	NM_001350121.2	c.1950T>C	p.Tyr650=	synonymous_variant	19/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEMA3C	ENST00000265361.8	c.2124T>C	p.Tyr708=	synonymous_variant	18/18	1	NM_006379.5	P1
SEMA3C	ENST00000419255.6	c.2124T>C	p.Tyr708=	synonymous_variant	18/18	2		P1

Frequencies

GnomAD3 genomes AF: 0.931 AC: 141627 AN: 152114 Hom.: 66682 Cov.: 32

Gnomad AFR AF: 0.777

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.976

Gnomad ASJ AF: 0.969

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.952

Gnomad FIN AF: 0.997

Gnomad MID AF: 0.972

Gnomad NFE AF: 0.994

Gnomad OTH AF: 0.956

GnomAD3 exomes AF: 0.973 AC: 244449 AN: 251216 Hom.: 119313 AF XY: 0.975 AC XY: 132422 AN XY: 135756

Gnomad AFR exome AF: 0.776

Gnomad AMR exome AF: 0.985

Gnomad ASJ exome AF: 0.975

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.959

Gnomad FIN exome AF: 0.996

Gnomad NFE exome AF: 0.992

Gnomad OTH exome AF: 0.981

GnomAD4 exome AF: 0.986 AC: 1440790 AN: 1461824 Hom.: 711076 Cov.: 68 AF XY: 0.985 AC XY: 716474 AN XY: 727216

Gnomad4 AFR exome AF: 0.768

Gnomad4 AMR exome AF: 0.983

Gnomad4 ASJ exome AF: 0.973

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.959

Gnomad4 FIN exome AF: 0.997

Gnomad4 NFE exome AF: 0.994

Gnomad4 OTH exome AF: 0.975

GnomAD4 genome AF: 0.931 AC: 141718 AN: 152230 Hom.: 66717 Cov.: 32 AF XY: 0.932 AC XY: 69399 AN XY: 74438

Gnomad4 AFR AF: 0.777

Gnomad4 AMR AF: 0.976

Gnomad4 ASJ AF: 0.969

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.951

Gnomad4 FIN AF: 0.997

Gnomad4 NFE AF: 0.994

Gnomad4 OTH AF: 0.956

Alfa AF: 0.962 Hom.: 38851

Bravo AF: 0.925

Asia WGS AF: 0.970 AC: 3372 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	-0.61
Cadd	Benign	7.0
Dann	Benign	0.48

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: rs1949971; hg19: chr7-80374342;