Genetic Variant CSF3R:p.Ala119Ser (chr1-36475383-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_000760.4(CSF3R):c.355G>T(p.Ala119Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. A119T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Consequence

CSF3R
NM_000760.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.54

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

hereditary neutrophilia
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
autosomal recessive severe congenital neutropenia due to CSF3R deficiency
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

CSF3R links:

ENSG00000297367 (HGNC:):

ENSG00000297367 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.746

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000760.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CSF3R	NM_000760.4	MANE Select	c.355G>T	p.Ala119Ser	missense	Exon 4 of 17	NP_000751.1	Q99062-1
CSF3R	NM_156039.3		c.355G>T	p.Ala119Ser	missense	Exon 4 of 17	NP_724781.1	Q99062-3
CSF3R	NM_172313.3		c.355G>T	p.Ala119Ser	missense	Exon 4 of 18	NP_758519.1	Q99062-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CSF3R	ENST00000373106.6	TSL:1 MANE Select	c.355G>T	p.Ala119Ser	missense	Exon 4 of 17	ENSP00000362198.2	Q99062-1
CSF3R	ENST00000373103.5	TSL:1	c.355G>T	p.Ala119Ser	missense	Exon 4 of 17	ENSP00000362195.1	Q99062-3
CSF3R	ENST00000373104.5	TSL:1	c.355G>T	p.Ala119Ser	missense	Exon 4 of 18	ENSP00000362196.1	Q99062-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal recessive severe congenital neutropenia due to CSF3R deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.82

M_CAP

Pathogenic

0.34

MetaRNN

Pathogenic

0.75

MetaSVM

Uncertain

0.23

MutationAssessor

Uncertain

2.0

PhyloP100

4.5

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.5

REVEL

Uncertain

0.40

Sift

Uncertain

0.012

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.66

MutPred

0.44

Gain of glycosylation at A119 (P = 0.0101)

MVP

0.94

MPC

0.95

ClinPred

0.98

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.35

gMVP

0.62

Mutation Taster

=57/43

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over