7-80745135-T-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_006379.5(SEMA3C):c.2015A>G(p.Asp672Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000843 in 1,613,896 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000084 (1 hom.)
• Consequence: SEMA3C NM_006379.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 5.86

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.02543965).
• BP6: Variant 7-80745135-T-C is Benign according to our data. Variant chr7-80745135-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 718913.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SEMA3C	NM_006379.5	c.2015A>G	p.Asp672Gly	missense_variant	18/18	ENST00000265361.8
SEMA3C	NM_001350120.2	c.2069A>G	p.Asp690Gly	missense_variant	18/18
SEMA3C	NM_001350121.2	c.1841A>G	p.Asp614Gly	missense_variant	19/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SEMA3C	ENST00000265361.8	c.2015A>G	p.Asp672Gly	missense_variant	18/18	1	NM_006379.5	P1
SEMA3C	ENST00000419255.6	c.2015A>G	p.Asp672Gly	missense_variant	18/18	2		P1

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000163 AC: 41 AN: 251176 Hom.: 0 AF XY: 0.000140 AC XY: 19 AN XY: 135734

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000348

Gnomad ASJ exome AF: 0.00248

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.0000841 AC: 123 AN: 1461738 Hom.: 1 Cov.: 34 AF XY: 0.0000811 AC XY: 59 AN XY: 727178

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000425

Gnomad4 ASJ exome AF: 0.00295

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152158 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74318

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000133 Hom.: 1

Bravo AF: 0.000106

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 14, 2023

The c.2015A>G (p.D672G) alteration is located in exon 18 (coding exon 17) of the SEMA3C gene. This alteration results from a A to G substitution at nucleotide position 2015, causing the aspartic acid (D) at amino acid position 672 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

SEMA3C-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 17, 2022

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
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.48
Cadd	Uncertain	24
Dann	Uncertain	0.98
DEOGEN2	Benign	0.061	T;T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.083
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.0091	T
MetaRNN	Benign	0.025	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.16	N;N
REVEL	Benign	0.086
Sift	Benign	0.37	T;T
Sift4G	Benign	0.39	T;T
Polyphen		0.0	B;B
Vest4		0.15
MVP		0.38
MPC		0.18
ClinPred		0.092	T
GERP RS		5.6
Varity_R		0.24
gMVP		0.53

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: rs148790247; hg19: chr7-80374451;