Genetic Variant NM_004186.5:c.37C>A (chr3-50159659-C-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_004186.5(SEMA3F):c.37C>A(p.Leu13Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,460,718 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. L13V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

SEMA3F
NM_004186.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.92

Publications

8 publications found

Variant links:

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

SEMA3F links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.21751735).

BS2

High AC in GnomAdExome4 at 7 AD gene.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SEMA3F	NM_004186.5	MANE Select	c.37C>A	p.Leu13Met	missense	Exon 2 of 19	NP_004177.3
SEMA3F	NM_001318800.2		c.37C>A	p.Leu13Met	missense	Exon 2 of 18	NP_001305729.1	Q13275-2
SEMA3F	NM_001318798.2		c.-135-33C>A		intron	N/A	NP_001305727.1	C9JPG5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SEMA3F	ENST00000002829.8	TSL:1 MANE Select	c.37C>A	p.Leu13Met	missense	Exon 2 of 19	ENSP00000002829.3	Q13275-1
SEMA3F	ENST00000434342.5	TSL:1	c.37C>A	p.Leu13Met	missense	Exon 2 of 18	ENSP00000409859.1	Q13275-2
SEMA3F	ENST00000413852.5	TSL:1	c.-135-33C>A		intron	N/A	ENSP00000388931.1	C9JPG5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000160

AC:

AN:

249582

AF XY:

0.0000222

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1460718

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726688

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33462

American (AMR)

AF:

0.00

AC:

AN:

44534

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39556

South Asian (SAS)

AF:

0.0000813

AC:

AN:

86146

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53142

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111622

Other (OTH)

AF:

0.00

AC:

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000247

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.027

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.10

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.61

M_CAP

Benign

0.025

MetaRNN

Benign

0.22

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.6

PhyloP100

2.9

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.73

REVEL

Benign

0.10

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.021

Polyphen

0.49

Vest4

0.48

MutPred

0.54

Loss of loop (P = 0.0073)

MVP

0.40

MPC

0.22

ClinPred

0.37

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.10

gMVP

0.16

Mutation Taster

=89/11

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over