rs142999683

Positions:

chr1-36475383-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4BS1_Supporting

The NM_000760.4(CSF3R):c.355G>A(p.Ala119Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000976 in 1,613,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A119S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00083 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00099 ( 0 hom. )

Consequence

CSF3R
NM_000760.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 4.54

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3797825).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000827 (126/152300) while in subpopulation NFE AF= 0.00129 (88/68024). AF 95% confidence interval is 0.00107. There are 0 homozygotes in gnomad4. There are 60 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CSF3R	NM_000760.4 linkuse as main transcript	c.355G>A	p.Ala119Thr	missense_variant	4/17	ENST00000373106.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CSF3R	ENST00000373106.6 linkuse as main transcript	c.355G>A	p.Ala119Thr	missense_variant	4/17	1	NM_000760.4	P1	Q99062-1

Frequencies

GnomAD3 genomes

AF:

0.000828

AC:

126

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00235

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00129

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.000633

AC:

159

AN:

251006

Hom.:

AF XY:

0.000685

AC XY:

AN XY:

135754

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00129

Gnomad NFE exome

AF:

0.00103

Gnomad OTH exome

AF:

0.000651

GnomAD4 exome

AF:

0.000991

AC:

1449

AN:

1461482

Hom.:

Cov.:

AF XY:

0.000950

AC XY:

691

AN XY:

727066

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.000786

Gnomad4 NFE exome

AF:

0.00121

Gnomad4 OTH exome

AF:

0.000646

GnomAD4 genome

AF:

0.000827

AC:

126

AN:

152300

Hom.:

Cov.:

AF XY:

0.000806

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00235

Gnomad4 NFE

AF:

0.00129

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.000944

Hom.:

Bravo

AF:

0.000586

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000593

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000981

EpiControl

AF:

0.000948

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 20, 2021

DNA sequence analysis of the CSF3R gene demonstrated a sequence change, c.355G>A, in exon 4 that results in an amino acid change, p.Ala119Thr. This sequence change has been described in the gnomAD database with a frequency of 0.12% in the Finnish European subpopulation (dbSNP rs142999683). This sequence change has also been previously described in one individual with multiple myeloma and one individual with acute lymphoblastic leukemia (PMID: 33108454). In addition, this sequence change has been observed in several samples tested in our laboratory with other indications besides cancer. The p.Ala119Thr change affects a highly conserved amino acid residue located in the Ig-like domain of the CSF3R protein. Functional studies show p.Ala119Thr disrupts G-CSF-induced CSF3R activation (PMID: 33108454). In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ala119Thr substitution. Due to the above information we are currently interpreting the p.Ala119Thr variant as a variant of unknown significance. -

Autosomal recessive severe congenital neutropenia due to CSF3R deficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 119 of the CSF3R protein (p.Ala119Thr). This variant is present in population databases (rs142999683, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with CSF3R-related conditions. ClinVar contains an entry for this variant (Variation ID: 566149). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CSF3R protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Jul 26, 2021

- -

Hereditary neutrophilia;C4310764:Autosomal recessive severe congenital neutropenia due to CSF3R deficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 07, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

0.020

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.14

T;.;.;T;.

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.85

.;.;T;T;T

M_CAP

Pathogenic

0.41

MetaRNN

Benign

0.38

T;T;T;T;T

MetaSVM

Uncertain

0.32

MutationAssessor

Uncertain

2.8

M;M;M;M;M

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.7

N;N;N;N;N

REVEL

Uncertain

0.49

Sift

Uncertain

0.0090

D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

1.0

D;D;D;D;D

Vest4

0.81

MVP

0.94

MPC

0.97

ClinPred

0.093

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.36

gMVP

0.69

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

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