1-36475633-G-T

Variant names:

• chr1-36475633-G-T
• rs3917954
• NM_000760.4:c.105C>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000760.4(CSF3R):​c.105C>A​(p.Ile35Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00354 in 1,606,998 control chromosomes in the GnomAD database, including 197 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. I35I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.018 (105 hom., cov: 31)
  • Exomes 𝑓: 0.0020 (92 hom.)
• Consequence: CSF3R NM_000760.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.417
• Publications: 4 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 1-36475633-G-T is Benign according to our data. Variant chr1-36475633-G-T is described in ClinVar as Benign. ClinVar VariationId is 256788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.417 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.062 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.105C>A	p.Ile35Ile	synonymous	Exon 4 of 17	NP_000751.1
	CSF3R	NM_156039.3		c.105C>A	p.Ile35Ile	synonymous	Exon 4 of 17	NP_724781.1
	CSF3R	NM_172313.3		c.105C>A	p.Ile35Ile	synonymous	Exon 4 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.105C>A	p.Ile35Ile	synonymous	Exon 4 of 17	ENSP00000362198.2
	CSF3R	ENST00000373103.5	TSL:1	c.105C>A	p.Ile35Ile	synonymous	Exon 4 of 17	ENSP00000362195.1
	CSF3R	ENST00000373104.5	TSL:1	c.105C>A	p.Ile35Ile	synonymous	Exon 4 of 18	ENSP00000362196.1

Frequencies

GnomAD3 genomes AF: 0.0180 AC: 2744 AN: 152062 Hom.: 104 Cov.: 31

Gnomad AFR AF: 0.0639

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.00484 AC: 1210 AN: 250060 AF XY: 0.00374

Gnomad AFR exome AF: 0.0660

Gnomad AMR exome AF: 0.00281

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.00361

GnomAD4 exome AF: 0.00202 AC: 2939 AN: 1454818 Hom.: 92 Cov.: 31 AF XY: 0.00180 AC XY: 1297 AN XY: 722174

African (AFR) AF: 0.0701 AC: 2338 AN: 33336

American (AMR) AF: 0.00339 AC: 151 AN: 44590

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26032

East Asian (EAS) AF: 0.00 AC: 0 AN: 39492

South Asian (SAS) AF: 0.000197 AC: 17 AN: 86088

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53330

Middle Eastern (MID) AF: 0.00351 AC: 19 AN: 5420

European-Non Finnish (NFE) AF: 0.000123 AC: 136 AN: 1106510

Other (OTH) AF: 0.00462 AC: 277 AN: 60020

GnomAD4 genome AF: 0.0181 AC: 2756 AN: 152180 Hom.: 105 Cov.: 31 AF XY: 0.0176 AC XY: 1311 AN XY: 74402

African (AFR) AF: 0.0640 AC: 2656 AN: 41502

American (AMR) AF: 0.00373 AC: 57 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68016

Other (OTH) AF: 0.0133 AC: 28 AN: 2110

Alfa AF: 0.00695 Hom.: 19

Bravo AF: 0.0207

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

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
BayesDel_noAF	Benign	-0.72
CADD	Benign	1.3
DANN	Benign	0.66
PhyloP100		-0.42
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs3917954; hg19: chr1-36941234;