chr1-36466441-G-C

Variant names:

• chr1-36466441-G-C
• rs369185814
• NM_000760.4:c.2427C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000760.4(CSF3R):​c.2427C>G​(p.Asp809Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D809D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CSF3R NM_000760.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.40
• Publications: 0 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: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ENSG00000297367 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13619208).

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.2427C>G	p.Asp809Glu	missense	Exon 17 of 17	NP_000751.1	Q99062-1
	CSF3R	NM_156039.3		c.2508C>G	p.Asp836Glu	missense	Exon 17 of 17	NP_724781.1	Q99062-3
	CSF3R	NM_172313.3		c.2247+180C>G		intron	N/A	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.2427C>G	p.Asp809Glu	missense	Exon 17 of 17	ENSP00000362198.2	Q99062-1
	CSF3R	ENST00000373103.5	TSL:1	c.2508C>G	p.Asp836Glu	missense	Exon 17 of 17	ENSP00000362195.1	Q99062-3
	CSF3R	ENST00000373104.5	TSL:1	c.2247+180C>G		intron	N/A	ENSP00000362196.1	Q99062-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461088 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726774

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44618

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26082

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86128

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5614

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111802

Other (OTH) AF: 0.00 AC: 0 AN: 60336

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	0.017
DANN	Uncertain	0.99
DEOGEN2	Benign	0.051	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		-1.4
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.070	N
REVEL	Benign	0.066
Sift	Benign	0.51	T
Sift4G	Benign	0.14	T
Polyphen		0.66	P
Vest4		0.11
MutPred		0.39		Loss of sheet (P = 0.0817)
MVP		0.61
MPC		0.34
ClinPred		0.17	T
GERP RS		-6.9
Varity_R		0.090
gMVP		0.12
Mutation Taster		=92/8	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

Other links and lift over

dbSNP: rs369185814; hg19: chr1-36932042;