chr3-50185493-T-G

Variant names:

• chr3-50185493-T-G
• rs1046956
• NM_004186.5:c.1507T>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004186.5(SEMA3F):​c.1507T>G​(p.Leu503Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L503M) has been classified as Benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: SEMA3F NM_004186.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.12
• Publications: 41 publications found

Genes affected

SEMA3F (HGNC:10728): (semaphorin 3F) This gene encodes a member of the semaphorin III family of secreted signaling proteins that are involved in axon guidance during neuronal development. The encoded protein contains an N-terminal Sema domain, an immunoglobulin loop and a C-terminal basic domain. This gene is expressed by the endothelial cells where it was found to act in an autocrine fashion to induce apoptosis, inhibit cell proliferation and survival, and function as an anti-tumorigenic agent. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2016]

SEMA3F Gene-Disease associations (from GenCC):

• hypogonadotropic hypogonadism

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.032608747).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004186.5. 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
	SEMA3F	NM_004186.5	MANE Select	c.1507T>G	p.Leu503Val	missense	Exon 14 of 19	NP_004177.3
	SEMA3F	NM_001318800.2		c.1414T>G	p.Leu472Val	missense	Exon 13 of 18	NP_001305729.1	Q13275-2
	SEMA3F	NM_001318798.2		c.1210T>G	p.Leu404Val	missense	Exon 13 of 18	NP_001305727.1	C9JPG5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SEMA3F	ENST00000002829.8	TSL:1 MANE Select	c.1507T>G	p.Leu503Val	missense	Exon 14 of 19	ENSP00000002829.3	Q13275-1
	SEMA3F	ENST00000434342.5	TSL:1	c.1414T>G	p.Leu472Val	missense	Exon 13 of 18	ENSP00000409859.1	Q13275-2
	SEMA3F	ENST00000413852.5	TSL:1	c.1210T>G	p.Leu404Val	missense	Exon 13 of 18	ENSP00000388931.1	C9JPG5

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 56

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 10867

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	16
DANN	Benign	0.69
DEOGEN2	Benign	0.0098	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.033	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.20	N
PhyloP100		1.1
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.045
Sift	Benign	0.41	T
Sift4G	Benign	0.46	T
Polyphen		0.0	B
Vest4		0.047
MutPred		0.36		Gain of catalytic residue at L503 (P = 0.0022)
MVP		0.14
MPC		0.81
ClinPred		0.037	T
GERP RS		0.29
Varity_R		0.022
gMVP		0.069
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs1046956; hg19: chr3-50222926;