NM_004186.5:c.92G>A

Variant names:

• chr3-50159714-G-A
• rs765808277
• NM_004186.5:c.92G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004186.5(SEMA3F):​c.92G>A​(p.Arg31Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,611,244 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SEMA3F NM_004186.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.64
• Publications: 1 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.92G>A	p.Arg31Gln	missense	Exon 2 of 19	NP_004177.3
	SEMA3F	NM_001318800.2		c.92G>A	p.Arg31Gln	missense	Exon 2 of 18	NP_001305729.1	Q13275-2
	SEMA3F	NM_001318798.2		c.-113G>A		5_prime_UTR	Exon 2 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.92G>A	p.Arg31Gln	missense	Exon 2 of 19	ENSP00000002829.3	Q13275-1
	SEMA3F	ENST00000434342.5	TSL:1	c.92G>A	p.Arg31Gln	missense	Exon 2 of 18	ENSP00000409859.1	Q13275-2
	SEMA3F	ENST00000413852.5	TSL:1	c.-113G>A		5_prime_UTR	Exon 2 of 18	ENSP00000388931.1	C9JPG5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459028 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726012

African (AFR) AF: 0.00 AC: 0 AN: 33390

American (AMR) AF: 0.00 AC: 0 AN: 44538

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39622

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86116

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52944

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1110260

Other (OTH) AF: 0.00 AC: 0 AN: 60286

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152216 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74358

African (AFR) AF: 0.0000241 AC: 1 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Uncertain	0.070	D
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.072	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		5.6
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.31
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.016	D
Polyphen		0.99	D
Vest4		0.63
MutPred		0.59		Loss of methylation at R31 (P = 0.0112)
MVP		0.70
MPC		0.75
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.28
gMVP		0.84
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs765808277; hg19: chr3-50197147;