chr3-50185493-T-A

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• 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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA3F	NM_004186.5	c.1507T>A	p.Leu503Met	missense_variant	Exon 14 of 19	ENST00000002829.8	NP_004177.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEMA3F	ENST00000002829.8	c.1507T>A	p.Leu503Met	missense_variant	Exon 14 of 19	1	NM_004186.5	ENSP00000002829.3
SEMA3F	ENST00000434342.5	c.1414T>A	p.Leu472Met	missense_variant	Exon 13 of 18	1		ENSP00000409859.1
SEMA3F	ENST00000413852.5	c.1210T>A	p.Leu404Met	missense_variant	Exon 13 of 18	1		ENSP00000388931.1
SEMA3F	ENST00000470737.1	n.*28T>A		downstream_gene_variant		5

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

GnomAD3 exomes AF: 0.741 AC: 185863 AN: 250686 Hom.: 70462 AF XY: 0.743 AC XY: 100704 AN XY: 135544

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 SAS exome AF: 0.878

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

Gnomad4 AFR exome AF: 0.601

Gnomad4 AMR exome AF: 0.807

Gnomad4 ASJ exome AF: 0.693

Gnomad4 EAS exome AF: 0.997

Gnomad4 SAS exome AF: 0.877

Gnomad4 FIN exome AF: 0.749

Gnomad4 NFE exome AF: 0.661

Gnomad4 OTH exome AF: 0.693

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

Gnomad4 AFR AF: 0.605

Gnomad4 AMR AF: 0.722

Gnomad4 ASJ AF: 0.703

Gnomad4 EAS AF: 0.991

Gnomad4 SAS AF: 0.884

Gnomad4 FIN AF: 0.752

Gnomad4 NFE AF: 0.663

Gnomad4 OTH AF: 0.677

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

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

SEMA3F-related disorder Benign:1

Apr 11, 2022

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

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;T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.12	T;T;T
MetaRNN	Benign	6.3e-7	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.26	.;N;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.56	N;N;N
REVEL	Benign	0.038
Sift	Benign	0.73	T;T;T
Sift4G	Benign	0.52	T;T;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

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

LitVar

Other links and lift over

dbSNP: rs1046956; hg19: chr3-50222926; COSMIC: COSV50029729; COSMIC: COSV50029729;