rs3917991

Variant names:

• chr1-36469204-C-G
• rs3917991
• NM_000760.4:c.1528G>C

Your query was ambiguous. Multiple possible variants found:

• chr1-36469204-C-G
• chr1-36469204-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000760.4(CSF3R):​c.1528G>C​(p.Asp510His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0189 in 1,613,928 control chromosomes in the GnomAD database, including 1,066 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. D510D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.053 (502 hom., cov: 33)
  • Exomes 𝑓: 0.015 (564 hom.)
• Consequence: CSF3R NM_000760.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.17
• Publications: 19 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017182529).
• BP6: Variant 1-36469204-C-G is Benign according to our data. Variant chr1-36469204-C-G is described in ClinVar as Benign. ClinVar VariationId is 256792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.15 is higher than 0.05.

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.1528G>C	p.Asp510His	missense	Exon 12 of 17	NP_000751.1	Q99062-1
	CSF3R	NM_156039.3		c.1528G>C	p.Asp510His	missense	Exon 12 of 17	NP_724781.1	Q99062-3
	CSF3R	NM_172313.3		c.1528G>C	p.Asp510His	missense	Exon 12 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.1528G>C	p.Asp510His	missense	Exon 12 of 17	ENSP00000362198.2	Q99062-1
	CSF3R	ENST00000373103.5	TSL:1	c.1528G>C	p.Asp510His	missense	Exon 12 of 17	ENSP00000362195.1	Q99062-3
	CSF3R	ENST00000373104.5	TSL:1	c.1528G>C	p.Asp510His	missense	Exon 12 of 18	ENSP00000362196.1	Q99062-4

Frequencies

GnomAD3 genomes AF: 0.0526 AC: 7999 AN: 152000 Hom.: 501 Cov.: 33

Gnomad AFR AF: 0.153

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0241

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00954

Gnomad FIN AF: 0.0241

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0132

Gnomad OTH AF: 0.0441

GnomAD2 exomes AF: 0.0217 AC: 5453 AN: 251466 AF XY: 0.0191

Gnomad AFR exome AF: 0.158

Gnomad AMR exome AF: 0.0141

Gnomad ASJ exome AF: 0.00238

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0235

Gnomad NFE exome AF: 0.0130

Gnomad OTH exome AF: 0.0187

GnomAD4 exome AF: 0.0154 AC: 22500 AN: 1461810 Hom.: 564 Cov.: 30 AF XY: 0.0148 AC XY: 10795 AN XY: 727214

African (AFR) AF: 0.159 AC: 5333 AN: 33466

American (AMR) AF: 0.0171 AC: 763 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00310 AC: 81 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00926 AC: 799 AN: 86258

European-Finnish (FIN) AF: 0.0233 AC: 1244 AN: 53420

Middle Eastern (MID) AF: 0.0199 AC: 115 AN: 5768

European-Non Finnish (NFE) AF: 0.0116 AC: 12892 AN: 1111948

Other (OTH) AF: 0.0211 AC: 1272 AN: 60392

GnomAD4 genome AF: 0.0527 AC: 8013 AN: 152118 Hom.: 502 Cov.: 33 AF XY: 0.0515 AC XY: 3827 AN XY: 74372

African (AFR) AF: 0.153 AC: 6337 AN: 41446

American (AMR) AF: 0.0240 AC: 367 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00954 AC: 46 AN: 4820

European-Finnish (FIN) AF: 0.0241 AC: 255 AN: 10600

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0132 AC: 897 AN: 68010

Other (OTH) AF: 0.0436 AC: 92 AN: 2110

Alfa AF: 0.0166 Hom.: 59

Bravo AF: 0.0568

TwinsUK AF: 0.0138 AC: 51

ALSPAC AF: 0.0127 AC: 49

ESP6500AA AF: 0.147 AC: 646

ESP6500EA AF: 0.0120 AC: 103

ExAC AF: 0.0241 AC: 2925

Asia WGS AF: 0.0120 AC: 43 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.42	T
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		2.2
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.16
Sift	Benign	0.047	D
Sift4G	Benign	0.087	T
Polyphen		0.98	D
Vest4		0.21
MPC		0.68
ClinPred		0.049	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.26
gMVP		0.76
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs3917991; hg19: chr1-36934805;