rs3918011

chr1-36475630-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000760.4(CSF3R):c.108C>T(p.Val36=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00256 in 1,607,150 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (8 hom.)
• Consequence: CSF3R NM_000760.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.669

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 1-36475630-G-A is Benign according to our data. Variant chr1-36475630-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 434838.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-36475630-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.669 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00183 (278/152246) while in subpopulation NFE AF= 0.00324 (220/68006). AF 95% confidence interval is 0.00288. There are 1 homozygotes in gnomad4. There are 133 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CSF3R	NM_000760.4	c.108C>T	p.Val36=	synonymous_variant	4/17	ENST00000373106.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CSF3R	ENST00000373106.6	c.108C>T	p.Val36=	synonymous_variant	4/17	1	NM_000760.4	P1

Frequencies

GnomAD3 genomes AF: 0.00183 AC: 278 AN: 152128 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00323

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00170 AC: 425 AN: 250372 Hom.: 3 AF XY: 0.00183 AC XY: 248 AN XY: 135310

Gnomad AFR exome AF: 0.000678

Gnomad AMR exome AF: 0.000666

Gnomad ASJ exome AF: 0.00251

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00311

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00264 AC: 3844 AN: 1454904 Hom.: 8 Cov.: 31 AF XY: 0.00253 AC XY: 1827 AN XY: 722162

Gnomad4 AFR exome AF: 0.000390

Gnomad4 AMR exome AF: 0.000605

Gnomad4 ASJ exome AF: 0.00219

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000300

Gnomad4 NFE exome AF: 0.00328

Gnomad4 OTH exome AF: 0.00167

GnomAD4 genome AF: 0.00183 AC: 278 AN: 152246 Hom.: 1 Cov.: 32 AF XY: 0.00179 AC XY: 133 AN XY: 74448

Gnomad4 AFR AF: 0.000722

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00324

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00294 Hom.: 0

Bravo AF: 0.00186

EpiCase AF: 0.00365

EpiControl AF: 0.00285

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	CSF3R: BP4, BP7, BS2 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 24, 2017

- -

Autosomal recessive severe congenital neutropenia due to CSF3R deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 21, 2024

- -

CSF3R-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 19, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	6.4
Dann	Benign	0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3918011; hg19: chr1-36941231; COSMIC: COSV58968496; COSMIC: COSV58968496;