NM_000760.4:c.1640G>T

Variant names:

• chr1-36468158-C-A
• rs138156467
• NM_000760.4:c.1640G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000760.4(CSF3R):​c.1640G>T​(p.Trp547Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,460,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CSF3R NM_000760.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.77
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ENSG00000297367 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSF3R	NM_000760.4	MANE Select	c.1640G>T	p.Trp547Leu	missense	Exon 13 of 17	NP_000751.1
	CSF3R	NM_156039.3		c.1640G>T	p.Trp547Leu	missense	Exon 13 of 17	NP_724781.1
	CSF3R	NM_172313.3		c.1640G>T	p.Trp547Leu	missense	Exon 13 of 18	NP_758519.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSF3R	ENST00000373106.6	TSL:1 MANE Select	c.1640G>T	p.Trp547Leu	missense	Exon 13 of 17	ENSP00000362198.2
	CSF3R	ENST00000373103.5	TSL:1	c.1640G>T	p.Trp547Leu	missense	Exon 13 of 17	ENSP00000362195.1
	CSF3R	ENST00000373104.5	TSL:1	c.1640G>T	p.Trp547Leu	missense	Exon 13 of 18	ENSP00000362196.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460948 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726754

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26016

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86138

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53334

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111494

Other (OTH) AF: 0.00 AC: 0 AN: 60364

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.60	D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.55	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		4.8
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-10	D
REVEL	Pathogenic	0.73
Sift	Benign	0.11	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.98	D
Vest4		0.84
MutPred		0.80		Loss of catalytic residue at L545 (P = 0.0026)
MVP		0.96
MPC		1.4
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.90
gMVP		0.93
Mutation Taster		=24/76	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs138156467; hg19: chr1-36933759;