1-36466446-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000760.4(CSF3R):c.2422G>A(p.Glu808Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00733 in 1,613,282 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E808G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0057 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0075 (55 hom.)
• Consequence: CSF3R NM_000760.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.42

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0042365193).
• BP6: Variant 1-36466446-C-T is Benign according to our data. Variant chr1-36466446-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 434833.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-36466446-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00571 (870/152340) while in subpopulation NFE AF= 0.00845 (575/68022). AF 95% confidence interval is 0.00788. There are 2 homozygotes in gnomad4. There are 403 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CSF3R	NM_000760.4	c.2422G>A	p.Glu808Lys	missense_variant	17/17	ENST00000373106.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CSF3R	ENST00000373106.6	c.2422G>A	p.Glu808Lys	missense_variant	17/17	1	NM_000760.4	P1

Frequencies

GnomAD3 genomes AF: 0.00572 AC: 870 AN: 152222 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00188

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00746

Gnomad ASJ AF: 0.0150

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00169

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00845

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.00653 AC: 1618 AN: 247678 Hom.: 8 AF XY: 0.00646 AC XY: 868 AN XY: 134298

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.00843

Gnomad ASJ exome AF: 0.0186

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00174

Gnomad FIN exome AF: 0.00188

Gnomad NFE exome AF: 0.00852

Gnomad OTH exome AF: 0.0120

GnomAD4 exome AF: 0.00750 AC: 10958 AN: 1460942 Hom.: 55 Cov.: 31 AF XY: 0.00732 AC XY: 5319 AN XY: 726710

Gnomad4 AFR exome AF: 0.00161

Gnomad4 AMR exome AF: 0.00828

Gnomad4 ASJ exome AF: 0.0165

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00207

Gnomad4 FIN exome AF: 0.00180

Gnomad4 NFE exome AF: 0.00836

Gnomad4 OTH exome AF: 0.00753

GnomAD4 genome AF: 0.00571 AC: 870 AN: 152340 Hom.: 2 Cov.: 32 AF XY: 0.00541 AC XY: 403 AN XY: 74490

Gnomad4 AFR AF: 0.00188

Gnomad4 AMR AF: 0.00745

Gnomad4 ASJ AF: 0.0150

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00169

Gnomad4 NFE AF: 0.00845

Gnomad4 OTH AF: 0.0113

Alfa AF: 0.00809 Hom.: 6

Bravo AF: 0.00620

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.00882 AC: 34

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00826 AC: 71

ExAC AF: 0.00577 AC: 700

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 23, 2016

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2023

CSF3R: BP4, BS1, BS2 -

Hereditary neutrophilia;C4310764:Autosomal recessive severe congenital neutropenia due to CSF3R deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 02, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.11	T;.;T
Eigen	Benign	0.051
Eigen_PC	Benign	0.027
FATHMM_MKL	Benign	0.14	N
MetaRNN	Benign	0.0042	T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.7	M;.;M
MutationTaster	Benign	0.84	D;D;D;D;D;D;D;D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.086
Sift	Benign	0.057	T;D;T
Sift4G	Uncertain	0.013	D;D;D
Polyphen		0.99	D;D;D
Vest4		0.099
MVP		0.82
MPC		0.96
ClinPred		0.021	T
GERP RS		3.7
Varity_R		0.20
gMVP		0.43

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

Publications

LitVar

Other links and lift over

dbSNP: rs146617729; hg19: chr1-36932047; COSMIC: COSV58963566; COSMIC: COSV58963566;