rs3918017

chr1-36472634-G-Achr1-36472634-G-T

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.726C>T(p.Ala242=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0159 in 1,611,898 control chromosomes in the GnomAD database, including 290 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (23 hom., cov: 32)
  • Exomes 𝑓: 0.016 (267 hom.)
• Consequence: CSF3R NM_000760.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.264

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=-0.86).
• BP6: Variant 1-36472634-G-A is Benign according to our data. Variant chr1-36472634-G-A is described in ClinVar as [Benign]. Clinvar id is 256795.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-36472634-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.264 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0131 (2001/152294) while in subpopulation AMR AF= 0.0235 (360/15304). AF 95% confidence interval is 0.0215. There are 23 homozygotes in gnomad4. There are 952 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CSF3R	NM_000760.4	c.726C>T	p.Ala242=	synonymous_variant	7/17	ENST00000373106.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CSF3R	ENST00000373106.6	c.726C>T	p.Ala242=	synonymous_variant	7/17	1	NM_000760.4	P1

Frequencies

GnomAD3 genomes AF: 0.0132 AC: 2002 AN: 152176 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.00328

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0236

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00791

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0196

Gnomad OTH AF: 0.0248

GnomAD3 exomes AF: 0.0131 AC: 3224 AN: 245884 Hom.: 38 AF XY: 0.0133 AC XY: 1789 AN XY: 134156

Gnomad AFR exome AF: 0.00270

Gnomad AMR exome AF: 0.0174

Gnomad ASJ exome AF: 0.00666

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00321

Gnomad FIN exome AF: 0.00592

Gnomad NFE exome AF: 0.0197

Gnomad OTH exome AF: 0.0193

GnomAD4 exome AF: 0.0162 AC: 23658 AN: 1459604 Hom.: 267 Cov.: 32 AF XY: 0.0161 AC XY: 11693 AN XY: 725794

Gnomad4 AFR exome AF: 0.00302

Gnomad4 AMR exome AF: 0.0172

Gnomad4 ASJ exome AF: 0.00644

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00377

Gnomad4 FIN exome AF: 0.00634

Gnomad4 NFE exome AF: 0.0189

Gnomad4 OTH exome AF: 0.0146

GnomAD4 genome AF: 0.0131 AC: 2001 AN: 152294 Hom.: 23 Cov.: 32 AF XY: 0.0128 AC XY: 952 AN XY: 74466

Gnomad4 AFR AF: 0.00327

Gnomad4 AMR AF: 0.0235

Gnomad4 ASJ AF: 0.00518

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.00791

Gnomad4 NFE AF: 0.0196

Gnomad4 OTH AF: 0.0246

Alfa AF: 0.0162 Hom.: 11

Bravo AF: 0.0146

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0224

EpiControl AF: 0.0255

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	2.7
Dann	Benign	0.29
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs3918017; hg19: chr1-36938235;