rs1046956

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr3-50185493-T-A
• chr3-50185493-T-C
• chr3-50185493-T-G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_004186.5(SEMA3F):​c.1507T>A​(p.Leu503Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.69 in 1,613,054 control chromosomes in the GnomAD database, including 388,839 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.68 (35489 hom., cov: 30)
  • Exomes 𝑓: 0.69 (353350 hom.)
• Consequence: SEMA3F NM_004186.5 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.3264076E-7).
• BP6: Variant 3-50185493-T-A is Benign according to our data. Variant chr3-50185493-T-A is described in ClinVar as Benign. ClinVar VariationId is 3059010.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.968 is higher than 0.05.

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>A	p.Leu503Met	missense	Exon 14 of 19	NP_004177.3
	SEMA3F	NM_001318800.2		c.1414T>A	p.Leu472Met	missense	Exon 13 of 18	NP_001305729.1	Q13275-2
	SEMA3F	NM_001318798.2		c.1210T>A	p.Leu404Met	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>A	p.Leu503Met	missense	Exon 14 of 19	ENSP00000002829.3	Q13275-1
	SEMA3F	ENST00000434342.5	TSL:1	c.1414T>A	p.Leu472Met	missense	Exon 13 of 18	ENSP00000409859.1	Q13275-2
	SEMA3F	ENST00000413852.5	TSL:1	c.1210T>A	p.Leu404Met	missense	Exon 13 of 18	ENSP00000388931.1	C9JPG5

Frequencies

GnomAD3 genomes AF: 0.679 AC: 102824 AN: 151432 Hom.: 35448 Cov.: 30

Gnomad AFR AF: 0.605

Gnomad AMI AF: 0.720

Gnomad AMR AF: 0.721

Gnomad ASJ AF: 0.703

Gnomad EAS AF: 0.991

Gnomad SAS AF: 0.884

Gnomad FIN AF: 0.752

Gnomad MID AF: 0.623

Gnomad NFE AF: 0.663

Gnomad OTH AF: 0.673

GnomAD2 exomes AF: 0.741 AC: 185863 AN: 250686 AF XY: 0.743

Gnomad AFR exome AF: 0.600

Gnomad AMR exome AF: 0.818

Gnomad ASJ exome AF: 0.688

Gnomad EAS exome AF: 0.994

Gnomad FIN exome AF: 0.752

Gnomad NFE exome AF: 0.665

Gnomad OTH exome AF: 0.705

GnomAD4 exome AF: 0.691 AC: 1009592 AN: 1461506 Hom.: 353350 Cov.: 56 AF XY: 0.696 AC XY: 505668 AN XY: 727050

African (AFR) AF: 0.601 AC: 20104 AN: 33474

American (AMR) AF: 0.807 AC: 36054 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.693 AC: 18098 AN: 26126

East Asian (EAS) AF: 0.997 AC: 39577 AN: 39696

South Asian (SAS) AF: 0.877 AC: 75645 AN: 86234

European-Finnish (FIN) AF: 0.749 AC: 40015 AN: 53398

Middle Eastern (MID) AF: 0.668 AC: 3846 AN: 5760

European-Non Finnish (NFE) AF: 0.661 AC: 734376 AN: 1111758

Other (OTH) AF: 0.693 AC: 41877 AN: 60388

GnomAD4 genome AF: 0.679 AC: 102918 AN: 151548 Hom.: 35489 Cov.: 30 AF XY: 0.688 AC XY: 50996 AN XY: 74070

African (AFR) AF: 0.605 AC: 24938 AN: 41190

American (AMR) AF: 0.722 AC: 11004 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.703 AC: 2436 AN: 3464

East Asian (EAS) AF: 0.991 AC: 5095 AN: 5142

South Asian (SAS) AF: 0.884 AC: 4262 AN: 4822

European-Finnish (FIN) AF: 0.752 AC: 7927 AN: 10538

Middle Eastern (MID) AF: 0.622 AC: 179 AN: 288

European-Non Finnish (NFE) AF: 0.663 AC: 45007 AN: 67858

Other (OTH) AF: 0.677 AC: 1418 AN: 2096

Alfa AF: 0.668 Hom.: 10867

Bravo AF: 0.668

TwinsUK AF: 0.660 AC: 2447

ALSPAC AF: 0.651 AC: 2509

ESP6500AA AF: 0.600 AC: 2645

ESP6500EA AF: 0.651 AC: 5598

ExAC AF: 0.737 AC: 89460

Asia WGS AF: 0.915 AC: 3180 AN: 3478

EpiCase AF: 0.662

EpiControl AF: 0.656

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	SEMA3F-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	13
DANN	Benign	0.094
DEOGEN2	Benign	0.0072	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.12	T
MetaRNN	Benign	6.3e-7	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.26	N
PhyloP100		1.1
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.56	N
REVEL	Benign	0.038
Sift	Benign	0.73	T
Sift4G	Benign	0.52	T
Polyphen		0.013	B
Vest4		0.059
MPC		0.78
ClinPred		0.000013	T
GERP RS		0.29
Varity_R		0.025
gMVP		0.068
Mutation Taster		=100/0	polymorphism (auto)

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; COSMIC: COSV50029729; COSMIC: COSV50029729;