7-80748939-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_006379.5(SEMA3C):c.1801A>G(p.Ile601Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000772 in 1,613,442 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0041 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (5 hom.)
• Consequence: SEMA3C NM_006379.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.21

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0076011717).
• BP6: Variant 7-80748939-T-C is Benign according to our data. Variant chr7-80748939-T-C is described in ClinVar as [Benign]. Clinvar id is 708481.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEMA3C	NM_006379.5	c.1801A>G	p.Ile601Val	missense_variant	17/18	ENST00000265361.8
SEMA3C	NM_001350120.2	c.1855A>G	p.Ile619Val	missense_variant	17/18
SEMA3C	NM_001350121.2	c.1627A>G	p.Ile543Val	missense_variant	18/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEMA3C	ENST00000265361.8	c.1801A>G	p.Ile601Val	missense_variant	17/18	1	NM_006379.5	P1
SEMA3C	ENST00000419255.6	c.1801A>G	p.Ile601Val	missense_variant	17/18	2		P1

Frequencies

GnomAD3 genomes AF: 0.00406 AC: 617 AN: 152126 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00113 AC: 283 AN: 250776 Hom.: 4 AF XY: 0.000804 AC XY: 109 AN XY: 135584

Gnomad AFR exome AF: 0.0155

Gnomad AMR exome AF: 0.000378

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000490

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.000427 AC: 624 AN: 1461198 Hom.: 5 Cov.: 33 AF XY: 0.000389 AC XY: 283 AN XY: 726934

Gnomad4 AFR exome AF: 0.0139

Gnomad4 AMR exome AF: 0.000560

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000353

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000450

Gnomad4 OTH exome AF: 0.00104

GnomAD4 genome AF: 0.00408 AC: 621 AN: 152244 Hom.: 5 Cov.: 32 AF XY: 0.00399 AC XY: 297 AN XY: 74454

Gnomad4 AFR AF: 0.0143

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00121 Hom.: 3

Bravo AF: 0.00471

ESP6500AA AF: 0.0111 AC: 49

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00145 AC: 176

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.0000594

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	12
Dann	Benign	0.53
DEOGEN2	Benign	0.058	T;T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.65	D
MetaRNN	Benign	0.0076	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.085	N;N
MutationTaster	Benign	0.90	D;D;D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.010	N;N
REVEL	Benign	0.081
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0020	B;B
Vest4		0.13
MVP		0.38
MPC		0.12
ClinPred		0.0030	T
GERP RS		4.2
Varity_R		0.047
gMVP		0.14

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: rs34020175; hg19: chr7-80378255;