rs3917996

chr1-36468114-A-G

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.1684T>C(p.Tyr562His) variant causes a missense change. The variant allele was found at a frequency of 0.00132 in 1,614,166 control chromosomes in the GnomAD database, including 28 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. Y562Y) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0066 (13 hom., cov: 33)
  • Exomes 𝑓: 0.00077 (15 hom.)
• Consequence: CSF3R NM_000760.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.71

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=0.010377973).
• BP6: Variant 1-36468114-A-G is Benign according to our data. Variant chr1-36468114-A-G is described in ClinVar as [Benign]. Clinvar id is 256793.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-36468114-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00661 (1006/152282) while in subpopulation AFR AF= 0.0226 (940/41554). AF 95% confidence interval is 0.0214. There are 13 homozygotes in gnomad4. There are 472 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CSF3R	NM_000760.4	c.1684T>C	p.Tyr562His	missense_variant	13/17	ENST00000373106.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CSF3R	ENST00000373106.6	c.1684T>C	p.Tyr562His	missense_variant	13/17	1	NM_000760.4	P1

Frequencies

GnomAD3 genomes AF: 0.00661 AC: 1006 AN: 152164 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.0227

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00222

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00623

GnomAD3 exomes AF: 0.00180 AC: 453 AN: 251436 Hom.: 3 AF XY: 0.00138 AC XY: 188 AN XY: 135888

Gnomad AFR exome AF: 0.0216

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.00228

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.000772 AC: 1128 AN: 1461884 Hom.: 15 Cov.: 32 AF XY: 0.000686 AC XY: 499 AN XY: 727246

Gnomad4 AFR exome AF: 0.0228

Gnomad4 AMR exome AF: 0.00141

Gnomad4 ASJ exome AF: 0.00172

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000112

Gnomad4 OTH exome AF: 0.00185

GnomAD4 genome AF: 0.00661 AC: 1006 AN: 152282 Hom.: 13 Cov.: 33 AF XY: 0.00634 AC XY: 472 AN XY: 74470

Gnomad4 AFR AF: 0.0226

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00151 Hom.: 1

Bravo AF: 0.00692

ESP6500AA AF: 0.0209 AC: 92

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00214 AC: 260

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000533

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 29, 2024

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.060
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D;.;.;D;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.97	D
MetaRNN	Benign	0.010	T;T;T;T;T
MetaSVM	Uncertain	0.19	D
MutationAssessor	Uncertain	2.8	M;M;M;M;M
MutationTaster	Benign	0.97	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-4.4	D;D;D;D;D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0030	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;D;D;D;D
Vest4		0.89
MVP		0.91
MPC		1.1
ClinPred		0.031	T
GERP RS		5.4
Varity_R		0.83
gMVP		0.95

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: rs3917996; hg19: chr1-36933715; COSMIC: COSV105898467; COSMIC: COSV105898467;