rs3918019

Positions:

• chr1-36471505-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.1213G>A​(p.Glu405Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00441 in 1,614,232 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (9 hom., cov: 33)
  • Exomes 𝑓: 0.0044 (16 hom.)
• Consequence: CSF3R NM_000760.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.44

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=0.006228626).
• BP6: Variant 1-36471505-C-T is Benign according to our data. Variant chr1-36471505-C-T is described in ClinVar as [Benign]. Clinvar id is 476293.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00467 (711/152340) while in subpopulation NFE AF= 0.00526 (358/68034). AF 95% confidence interval is 0.00481. There are 9 homozygotes in gnomad4. There are 441 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CSF3R	NM_000760.4	c.1213G>A	p.Glu405Lys	missense_variant	10/17	ENST00000373106.6	NP_000751.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CSF3R	ENST00000373106.6	c.1213G>A	p.Glu405Lys	missense_variant	10/17	1	NM_000760.4	ENSP00000362198	P1

Frequencies

GnomAD3 genomes AF: 0.00467 AC: 711 AN: 152222 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.000844

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0271

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00526

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00532 AC: 1338 AN: 251484 Hom.: 6 AF XY: 0.00553 AC XY: 752 AN XY: 135920

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.00188

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.0257

Gnomad NFE exome AF: 0.00619

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00438 AC: 6409 AN: 1461892 Hom.: 16 Cov.: 34 AF XY: 0.00427 AC XY: 3104 AN XY: 727246

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.000693

Gnomad4 ASJ exome AF: 0.00149

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.0233

Gnomad4 NFE exome AF: 0.00437

Gnomad4 OTH exome AF: 0.00333

GnomAD4 genome AF: 0.00467 AC: 711 AN: 152340 Hom.: 9 Cov.: 33 AF XY: 0.00592 AC XY: 441 AN XY: 74492

Gnomad4 AFR AF: 0.000842

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0271

Gnomad4 NFE AF: 0.00526

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00443 Hom.: 4

Bravo AF: 0.00247

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00430 AC: 37

ExAC AF: 0.00514 AC: 624

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00447

EpiControl AF: 0.00492

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

Genetic Services Laboratory, University of Chicago

Jun 12, 2018

- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.099	T;.;.;T;.
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.093	N
LIST_S2	Uncertain	0.88	.;.;D;D;D
MetaRNN	Benign	0.0062	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;L;L;L;L
MutationTaster	Benign	0.99	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.79	N;N;N;N;N
REVEL	Benign	0.037
Sift	Benign	0.42	T;T;T;T;T
Sift4G	Uncertain	0.059	T;T;T;T;T
Polyphen		0.65	P;B;P;P;B
Vest4		0.20
MVP		0.43
MPC		0.37
ClinPred		0.0074	T
GERP RS		3.3
Varity_R		0.055
gMVP		0.39

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

Publications

LitVar

Other links and lift over

dbSNP: rs3918019; hg19: chr1-36937106; COSMIC: COSV105898437; COSMIC: COSV105898437;