rs148104401

Positions:

chr1-36467938-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000760.4(CSF3R):c.1748G>A(p.Arg583His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000282 in 1,614,192 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0015 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00015 ( 2 hom. )

Consequence

CSF3R
NM_000760.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: -1.15

Variant links:

Genes affected

CSF3R (HGNC:2439): (colony stimulating factor 3 receptor) The protein encoded by this gene is the receptor for colony stimulating factor 3, a cytokine that controls the production, differentiation, and function of granulocytes. The encoded protein, which is a member of the family of cytokine receptors, may also function in some cell surface adhesion or recognition processes. Alternatively spliced transcript variants have been described. Mutations in this gene are a cause of Kostmann syndrome, also known as severe congenital neutropenia. [provided by RefSeq, Aug 2010]

CSF3R links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0031633973).

BP6

Variant 1-36467938-C-T is Benign according to our data. Variant chr1-36467938-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 432323.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00152 (232/152338) while in subpopulation AFR AF= 0.00512 (213/41578). AF 95% confidence interval is 0.00456. There are 1 homozygotes in gnomad4. There are 111 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CSF3R	NM_000760.4 linkuse as main transcript	c.1748G>A	p.Arg583His	missense_variant	14/17	ENST00000373106.6	NP_000751.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CSF3R	ENST00000373106.6 linkuse as main transcript	c.1748G>A	p.Arg583His	missense_variant	14/17	1	NM_000760.4	ENSP00000362198	P1	Q99062-1

Frequencies

GnomAD3 genomes

AF:

0.00146

AC:

222

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00490

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

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

GnomAD3 exomes

AF:

0.000470

AC:

118

AN:

251256

Hom.:

AF XY:

0.000375

AC XY:

AN XY:

135846

show subpopulations

Gnomad AFR exome

AF:

0.00531

Gnomad AMR exome

AF:

0.000549

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000153

AC:

223

AN:

1461854

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.00397

Gnomad4 AMR exome

AF:

0.000537

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.000712

GnomAD4 genome

AF:

0.00152

AC:

232

AN:

152338

Hom.:

Cov.:

AF XY:

0.00149

AC XY:

111

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.00512

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000288

Hom.:

Bravo

AF:

0.00201

ESP6500AA

AF:

0.00590

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000593

AC:

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 05, 2017

The R583H variant in the CSF3R gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R583H variant is observed in 61/10340 (0.589%) alleles from individuals of African background in the ExAC dataset (Lek et al., 2016). The R583H variant is a conservative amino acid substitution, which occurs at a position that is not conserved. In silico analysis predicts this variant likely does not alter the protein structure/function. We interpret R583H as a variant of uncertain significance. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 22, 2017

- -

Autosomal recessive severe congenital neutropenia due to CSF3R deficiency

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

- -

CSF3R-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 24, 2022

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

0.055

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.60

CADD

Benign

0.18

DANN

Benign

0.82

DEOGEN2

Benign

0.062

T;.;.;T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0090

LIST_S2

Benign

0.54

.;.;T;T;T

M_CAP

Benign

0.018

MetaRNN

Benign

0.0032

T;T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-1.3

N;N;N;N;N

MutationTaster

Benign

1.0

N;N;N;N;N;N;N;N

PrimateAI

Benign

0.20

PROVEAN

Benign

0.050

N;N;N;N;N

REVEL

Benign

0.045

Sift

Benign

0.57

T;T;T;T;T

Sift4G

Benign

1.0

T;T;T;T;T

Polyphen

0.0020

B;B;B;B;B

Vest4

0.029

MVP

0.42

MPC

0.36

ClinPred

0.0019

GERP RS

-4.8

Varity_R

0.020

gMVP

0.59

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over