rs139332126

Variant names:

• chr1-36473802-C-G
• rs139332126
• NM_000760.4:c.447G>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000760.4(CSF3R):​c.447G>C​(p.Glu149Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00439 in 1,614,236 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E149K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0029 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0045 (32 hom.)
• Consequence: CSF3R NM_000760.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: -0.195
• Publications: 12 publications found

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)

ENSG00000297367 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003936529).
• BP6: Variant 1-36473802-C-G is Benign according to our data. Variant chr1-36473802-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 434837.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00294 (448/152356) while in subpopulation NFE AF = 0.00497 (338/68042). AF 95% confidence interval is 0.00453. There are 0 homozygotes in GnomAd4. There are 183 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 32 AD,AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSF3R	NM_000760.4	MANE Select	c.447G>C	p.Glu149Asp	missense	Exon 5 of 17	NP_000751.1	Q99062-1
	CSF3R	NM_156039.3		c.447G>C	p.Glu149Asp	missense	Exon 5 of 17	NP_724781.1	Q99062-3
	CSF3R	NM_172313.3		c.447G>C	p.Glu149Asp	missense	Exon 5 of 18	NP_758519.1	Q99062-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSF3R	ENST00000373106.6	TSL:1 MANE Select	c.447G>C	p.Glu149Asp	missense	Exon 5 of 17	ENSP00000362198.2	Q99062-1
	CSF3R	ENST00000373103.5	TSL:1	c.447G>C	p.Glu149Asp	missense	Exon 5 of 17	ENSP00000362195.1	Q99062-3
	CSF3R	ENST00000373104.5	TSL:1	c.447G>C	p.Glu149Asp	missense	Exon 5 of 18	ENSP00000362196.1	Q99062-4

Frequencies

GnomAD3 genomes AF: 0.00294 AC: 448 AN: 152238 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00497

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00294 AC: 738 AN: 251422 AF XY: 0.00315

Gnomad AFR exome AF: 0.000984

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.00278

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000555

Gnomad NFE exome AF: 0.00470

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00454 AC: 6637 AN: 1461880 Hom.: 32 Cov.: 31 AF XY: 0.00439 AC XY: 3190 AN XY: 727244

African (AFR) AF: 0.000657 AC: 22 AN: 33480

American (AMR) AF: 0.00172 AC: 77 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00302 AC: 79 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00234 AC: 202 AN: 86248

European-Finnish (FIN) AF: 0.000543 AC: 29 AN: 53418

Middle Eastern (MID) AF: 0.00295 AC: 17 AN: 5768

European-Non Finnish (NFE) AF: 0.00532 AC: 5921 AN: 1112010

Other (OTH) AF: 0.00480 AC: 290 AN: 60396

GnomAD4 genome AF: 0.00294 AC: 448 AN: 152356 Hom.: 0 Cov.: 32 AF XY: 0.00246 AC XY: 183 AN XY: 74498

African (AFR) AF: 0.00108 AC: 45 AN: 41588

American (AMR) AF: 0.00216 AC: 33 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4824

European-Finnish (FIN) AF: 0.000659 AC: 7 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00497 AC: 338 AN: 68042

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00418 Hom.: 3

Bravo AF: 0.00289

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00465 AC: 40

ExAC AF: 0.00299 AC: 363

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00458

EpiControl AF: 0.00516

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	-	3	not specified (3)
-	-	1	Autosomal recessive severe congenital neutropenia due to CSF3R deficiency (1)
-	-	1	CSF3R-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.5
DANN	Benign	0.51
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.32	N
PhyloP100		-0.20
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.015
Sift	Benign	1.0	T
Sift4G	Benign	0.61	T
Polyphen		0.0	B
Vest4		0.13
MutPred		0.34		Loss of sheet (P = 0.0817)
MVP		0.32
MPC		0.26
ClinPred		0.0010	T
GERP RS		-3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.052
gMVP		0.33
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs139332126; hg19: chr1-36939403; COSMIC: COSV58963849;