rs3917996

Variant names:

• chr1-36468114-A-G
• rs3917996
• NM_000760.4:c.1684T>C

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.1684T>C​(p.Tyr562His) variant causes a missense change. The variant allele was found at a frequency of 0.00132 in 1,614,166 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. Y562Y) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0066 (13 hom., cov: 33)
  • Exomes 𝑓: 0.00077 (15 hom.)
• Consequence: CSF3R NM_000760.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 5.71
• Publications: 8 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010377973).
• BP6: Variant 1-36468114-A-G is Benign according to our data. Variant chr1-36468114-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256793.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00661 (1006/152282) while in subpopulation AFR AF = 0.0226 (940/41554). AF 95% confidence interval is 0.0214. There are 13 homozygotes in GnomAd4. There are 472 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 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.1684T>C	p.Tyr562His	missense	Exon 13 of 17	NP_000751.1
	CSF3R	NM_156039.3		c.1684T>C	p.Tyr562His	missense	Exon 13 of 17	NP_724781.1
	CSF3R	NM_172313.3		c.1684T>C	p.Tyr562His	missense	Exon 13 of 18	NP_758519.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSF3R	ENST00000373106.6	TSL:1 MANE Select	c.1684T>C	p.Tyr562His	missense	Exon 13 of 17	ENSP00000362198.2
	CSF3R	ENST00000373103.5	TSL:1	c.1684T>C	p.Tyr562His	missense	Exon 13 of 17	ENSP00000362195.1
	CSF3R	ENST00000373104.5	TSL:1	c.1684T>C	p.Tyr562His	missense	Exon 13 of 18	ENSP00000362196.1

Frequencies

GnomAD3 genomes AF: 0.00661 AC: 1006 AN: 152164 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.0227

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00222

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00623

GnomAD2 exomes AF: 0.00180 AC: 453 AN: 251436 AF XY: 0.00138

Gnomad AFR exome AF: 0.0216

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.00228

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.000772 AC: 1128 AN: 1461884 Hom.: 15 Cov.: 32 AF XY: 0.000686 AC XY: 499 AN XY: 727246

African (AFR) AF: 0.0228 AC: 765 AN: 33480

American (AMR) AF: 0.00141 AC: 63 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00172 AC: 45 AN: 26136

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

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00260 AC: 15 AN: 5768

European-Non Finnish (NFE) AF: 0.000112 AC: 124 AN: 1112006

Other (OTH) AF: 0.00185 AC: 112 AN: 60396

GnomAD4 genome AF: 0.00661 AC: 1006 AN: 152282 Hom.: 13 Cov.: 33 AF XY: 0.00634 AC XY: 472 AN XY: 74470

African (AFR) AF: 0.0226 AC: 940 AN: 41554

American (AMR) AF: 0.00222 AC: 34 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68018

Other (OTH) AF: 0.00616 AC: 13 AN: 2110

Alfa AF: 0.00232 Hom.: 10

Bravo AF: 0.00692

ESP6500AA AF: 0.0209 AC: 92

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00214 AC: 260

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000533

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Autosomal recessive severe congenital neutropenia due to CSF3R deficiency (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.85	D
MetaRNN	Benign	0.010	T
MetaSVM	Uncertain	0.19	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		5.7
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.89
MVP		0.91
MPC		1.1
ClinPred		0.031	T
GERP RS		5.4
Varity_R		0.83
gMVP		0.95
Mutation Taster		=96/4	polymorphism

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: rs3917996; hg19: chr1-36933715; COSMIC: COSV105898467;