3-50159677-T-C

Variant names:

• chr3-50159677-T-C
• rs140721147
• NM_004186.5:c.55T>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_004186.5(SEMA3F):​c.55T>C​(p.Ser19Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000142 in 1,613,256 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S19F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00080 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000073 (1 hom.)
• Consequence: SEMA3F NM_004186.5 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 2.28

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

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006094694).
• BP6: Variant 3-50159677-T-C is Benign according to our data. Variant chr3-50159677-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3054991.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAd4 at 122 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SEMA3F	NM_004186.5	c.55T>C	p.Ser19Pro	missense_variant	Exon 2 of 19	ENST00000002829.8	NP_004177.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SEMA3F	ENST00000002829.8	c.55T>C	p.Ser19Pro	missense_variant	Exon 2 of 19	1	NM_004186.5	ENSP00000002829.3

Frequencies

GnomAD3 genomes AF: 0.000802 AC: 122 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00287

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000164 AC: 41 AN: 249868 AF XY: 0.000118

Gnomad AFR exome AF: 0.00236

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000732 AC: 107 AN: 1460932 Hom.: 1 Cov.: 31 AF XY: 0.0000509 AC XY: 37 AN XY: 726784

Gnomad4 AFR exome AF: 0.00299 AC: 100 AN: 33462

Gnomad4 AMR exome AF: 0.0000448 AC: 2 AN: 44598

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26128

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39608

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86162

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53104

Gnomad4 NFE exome AF: 0.00000180 AC: 2 AN: 1111736

Gnomad4 Remaining exome AF: 0.0000497 AC: 3 AN: 60368

GnomAD4 genome AF: 0.000801 AC: 122 AN: 152324 Hom.: 0 Cov.: 33 AF XY: 0.000792 AC XY: 59 AN XY: 74486

Gnomad4 AFR AF: 0.00286 AC: 0.00286264 AN: 0.00286264

Gnomad4 AMR AF: 0.0000653 AC: 0.0000653424 AN: 0.0000653424

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000147 AC: 0.0000146994 AN: 0.0000146994

Gnomad4 OTH AF: 0.000473 AC: 0.000473485 AN: 0.000473485

Alfa AF: 0.000572 Hom.: 0

Bravo AF: 0.000873

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000231 AC: 28

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

SEMA3F-related disorder Benign:1

Feb 15, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely 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	0.067
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	21
DANN	Benign	0.91
DEOGEN2	Benign	0.013	T;T;T;.;.
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.54	T;T;T;T;T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.0061	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	.;.;N;.;N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.73	N;N;N;N;N
REVEL	Benign	0.14
Sift	Benign	0.27	T;T;T;T;T
Sift4G	Benign	0.23	T;T;T;T;T
Polyphen		0.0	.;.;B;.;.
Vest4		0.33, 0.34
MVP		0.72
MPC		0.30
ClinPred		0.015	T
GERP RS		1.9
Varity_R		0.075
gMVP		0.24
Mutation Taster		=95/5	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

Publications

LitVar

Other links and lift over

dbSNP: rs140721147; hg19: chr3-50197110;