rs1527482

Variant names:

• chr7-80798214-C-T
• rs1527482
• NM_006379.5:c.1009G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-80798214-C-T
• chr7-80798214-C-A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP3 BP4_Strong BP6_Very_Strong BA1

The NM_006379.5(SEMA3C):​c.1009G>A​(p.Val337Met) variant causes a missense change. The variant allele was found at a frequency of 0.0126 in 1,488,400 control chromosomes in the GnomAD database, including 591 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (63 hom., cov: 32)
  • Exomes 𝑓: 0.012 (528 hom.)
• Consequence: SEMA3C NM_006379.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 6.16
• Publications: 15 publications found

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

Our verdict: Benign. The variant received -19 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 6: AlphaMissense, Cadd, Eigen, FATHMM_MKL, MutationAssessor, PrimateAI [when BayesDel_addAF, max_spliceai, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.005048603).
• BP6: Variant 7-80798214-C-T is Benign according to our data. Variant chr7-80798214-C-T is described in ClinVar as Benign. ClinVar VariationId is 1272490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0647 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006379.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEMA3C	NM_006379.5	MANE Select	c.1009G>A	p.Val337Met	missense	Exon 11 of 18	NP_006370.1	Q99985-1
	SEMA3C	NM_001350120.2		c.1063G>A	p.Val355Met	missense	Exon 11 of 18	NP_001337049.1
	SEMA3C	NM_001350121.2		c.835G>A	p.Val279Met	missense	Exon 12 of 19	NP_001337050.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEMA3C	ENST00000265361.8	TSL:1 MANE Select	c.1009G>A	p.Val337Met	missense	Exon 11 of 18	ENSP00000265361.3	Q99985-1
	SEMA3C	ENST00000953788.1		c.1183G>A	p.Val395Met	missense	Exon 13 of 20	ENSP00000623847.1
	SEMA3C	ENST00000953787.1		c.1126G>A	p.Val376Met	missense	Exon 12 of 19	ENSP00000623846.1

Frequencies

GnomAD3 genomes AF: 0.0144 AC: 2185 AN: 151890 Hom.: 63 Cov.: 32

Gnomad AFR AF: 0.00285

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0677

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0602

Gnomad SAS AF: 0.0382

Gnomad FIN AF: 0.000949

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00715

Gnomad OTH AF: 0.0191

GnomAD2 exomes AF: 0.0284 AC: 4958 AN: 174880 AF XY: 0.0249

Gnomad AFR exome AF: 0.00310

Gnomad AMR exome AF: 0.175

Gnomad ASJ exome AF: 0.00170

Gnomad EAS exome AF: 0.0711

Gnomad FIN exome AF: 0.000701

Gnomad NFE exome AF: 0.00639

Gnomad OTH exome AF: 0.0254

GnomAD4 exome AF: 0.0124 AC: 16509 AN: 1336392 Hom.: 528 Cov.: 31 AF XY: 0.0126 AC XY: 8305 AN XY: 658144

African (AFR) AF: 0.00146 AC: 40 AN: 27346

American (AMR) AF: 0.149 AC: 3739 AN: 25138

Ashkenazi Jewish (ASJ) AF: 0.00114 AC: 25 AN: 21984

East Asian (EAS) AF: 0.0746 AC: 2506 AN: 33586

South Asian (SAS) AF: 0.0378 AC: 2530 AN: 66874

European-Finnish (FIN) AF: 0.00126 AC: 64 AN: 50702

Middle Eastern (MID) AF: 0.00996 AC: 53 AN: 5320

European-Non Finnish (NFE) AF: 0.00647 AC: 6796 AN: 1051020

Other (OTH) AF: 0.0139 AC: 756 AN: 54422

GnomAD4 genome AF: 0.0145 AC: 2197 AN: 152008 Hom.: 63 Cov.: 32 AF XY: 0.0158 AC XY: 1173 AN XY: 74300

African (AFR) AF: 0.00285 AC: 118 AN: 41454

American (AMR) AF: 0.0681 AC: 1040 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.0610 AC: 315 AN: 5168

South Asian (SAS) AF: 0.0384 AC: 185 AN: 4814

European-Finnish (FIN) AF: 0.000949 AC: 10 AN: 10540

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00715 AC: 486 AN: 67976

Other (OTH) AF: 0.0189 AC: 40 AN: 2112

Alfa AF: 0.0120 Hom.: 133

Bravo AF: 0.0192

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.00752 AC: 29

ESP6500AA AF: 0.00522 AC: 23

ESP6500EA AF: 0.00488 AC: 42

ExAC AF: 0.0264 AC: 3208

Asia WGS AF: 0.0530 AC: 185 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	SEMA3C-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.0050	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Pathogenic	4.0	H
PhyloP100		6.2
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.35
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.77
MPC		0.58
ClinPred		0.089	T
GERP RS		5.7
Varity_R		0.90
gMVP		0.81
Mutation Taster		=69/31	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1527482; hg19: chr7-80427530; COSMIC: COSV54853624;