rs3918018

Variant names:

• chr1-36472277-C-T
• rs3918018
• NM_000760.4:c.958G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000760.4(CSF3R):​c.958G>A​(p.Asp320Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0256 in 1,614,142 control chromosomes in the GnomAD database, including 624 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (39 hom., cov: 32)
  • Exomes 𝑓: 0.026 (585 hom.)
• Consequence: CSF3R NM_000760.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.123
• Publications: 21 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=0.005912125).
• BP6: Variant 1-36472277-C-T is Benign according to our data. Variant chr1-36472277-C-T is described in ClinVar as Benign. ClinVar VariationId is 256796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0204 (3111/152256) while in subpopulation NFE AF = 0.0323 (2194/68012). AF 95% confidence interval is 0.0311. There are 39 homozygotes in GnomAd4. There are 1483 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 39 AR,AD 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.958G>A	p.Asp320Asn	missense	Exon 8 of 17	NP_000751.1	Q99062-1
	CSF3R	NM_156039.3		c.958G>A	p.Asp320Asn	missense	Exon 8 of 17	NP_724781.1	Q99062-3
	CSF3R	NM_172313.3		c.958G>A	p.Asp320Asn	missense	Exon 8 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.958G>A	p.Asp320Asn	missense	Exon 8 of 17	ENSP00000362198.2	Q99062-1
	CSF3R	ENST00000373103.5	TSL:1	c.958G>A	p.Asp320Asn	missense	Exon 8 of 17	ENSP00000362195.1	Q99062-3
	CSF3R	ENST00000373104.5	TSL:1	c.958G>A	p.Asp320Asn	missense	Exon 8 of 18	ENSP00000362196.1	Q99062-4

Frequencies

GnomAD3 genomes AF: 0.0205 AC: 3113 AN: 152138 Hom.: 39 Cov.: 32

Gnomad AFR AF: 0.00628

Gnomad AMI AF: 0.0406

Gnomad AMR AF: 0.0171

Gnomad ASJ AF: 0.0219

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0213

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0323

Gnomad OTH AF: 0.0182

GnomAD2 exomes AF: 0.0188 AC: 4725 AN: 251056 AF XY: 0.0187

Gnomad AFR exome AF: 0.00505

Gnomad AMR exome AF: 0.0144

Gnomad ASJ exome AF: 0.0275

Gnomad EAS exome AF: 0.000544

Gnomad FIN exome AF: 0.0205

Gnomad NFE exome AF: 0.0281

Gnomad OTH exome AF: 0.0222

GnomAD4 exome AF: 0.0262 AC: 38243 AN: 1461886 Hom.: 585 Cov.: 32 AF XY: 0.0256 AC XY: 18615 AN XY: 727246

African (AFR) AF: 0.00469 AC: 157 AN: 33480

American (AMR) AF: 0.0144 AC: 645 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0248 AC: 647 AN: 26136

East Asian (EAS) AF: 0.000327 AC: 13 AN: 39700

South Asian (SAS) AF: 0.00260 AC: 224 AN: 86254

European-Finnish (FIN) AF: 0.0205 AC: 1097 AN: 53418

Middle Eastern (MID) AF: 0.0281 AC: 162 AN: 5768

European-Non Finnish (NFE) AF: 0.0304 AC: 33849 AN: 1112010

Other (OTH) AF: 0.0240 AC: 1449 AN: 60396

GnomAD4 genome AF: 0.0204 AC: 3111 AN: 152256 Hom.: 39 Cov.: 32 AF XY: 0.0199 AC XY: 1483 AN XY: 74436

African (AFR) AF: 0.00623 AC: 259 AN: 41554

American (AMR) AF: 0.0171 AC: 262 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0219 AC: 76 AN: 3472

East Asian (EAS) AF: 0.000582 AC: 3 AN: 5158

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4824

European-Finnish (FIN) AF: 0.0213 AC: 226 AN: 10616

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0323 AC: 2194 AN: 68012

Other (OTH) AF: 0.0180 AC: 38 AN: 2110

Alfa AF: 0.0252 Hom.: 196

Bravo AF: 0.0194

TwinsUK AF: 0.0289 AC: 107

ALSPAC AF: 0.0296 AC: 114

ESP6500AA AF: 0.00635 AC: 28

ESP6500EA AF: 0.0306 AC: 263

ExAC AF: 0.0189 AC: 2297

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0283

EpiControl AF: 0.0261

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	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	0.072
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	8.7
DANN	Benign	0.88
DEOGEN2	Benign	0.17	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.41	T
MetaRNN	Benign	0.0059	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.57	N
PhyloP100		-0.12
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.091
Sift	Benign	0.39	T
Sift4G	Benign	0.58	T
Polyphen		0.0	B
Vest4		0.038
MPC		0.28
ClinPred		0.0051	T
GERP RS		-5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.17
gMVP		0.28
Mutation Taster		=100/0	polymorphism (auto)

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: rs3918018; hg19: chr1-36937878; COSMIC: COSV58967191; COSMIC: COSV58967191;