rs3917991

Positions:

• chr1-36469204-C-G
• chr1-36469204-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000760.4(CSF3R):​c.1528G>C​(p.Asp510His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0189 in 1,613,928 control chromosomes in the GnomAD database, including 1,066 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.053 (502 hom., cov: 33)
  • Exomes 𝑓: 0.015 (564 hom.)
• Consequence: CSF3R NM_000760.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.17

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=0.0017182529).
• BP6: Variant 1-36469204-C-G is Benign according to our data. Variant chr1-36469204-C-G is described in ClinVar as [Benign]. Clinvar id is 256792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-36469204-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.15 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CSF3R	NM_000760.4	c.1528G>C	p.Asp510His	missense_variant	12/17	ENST00000373106.6	NP_000751.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CSF3R	ENST00000373106.6	c.1528G>C	p.Asp510His	missense_variant	12/17	1	NM_000760.4	ENSP00000362198	P1

Frequencies

GnomAD3 genomes AF: 0.0526 AC: 7999 AN: 152000 Hom.: 501 Cov.: 33

Gnomad AFR AF: 0.153

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0241

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00954

Gnomad FIN AF: 0.0241

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0132

Gnomad OTH AF: 0.0441

GnomAD3 exomes AF: 0.0217 AC: 5453 AN: 251466 Hom.: 220 AF XY: 0.0191 AC XY: 2599 AN XY: 135912

Gnomad AFR exome AF: 0.158

Gnomad AMR exome AF: 0.0141

Gnomad ASJ exome AF: 0.00238

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00888

Gnomad FIN exome AF: 0.0235

Gnomad NFE exome AF: 0.0130

Gnomad OTH exome AF: 0.0187

GnomAD4 exome AF: 0.0154 AC: 22500 AN: 1461810 Hom.: 564 Cov.: 30 AF XY: 0.0148 AC XY: 10795 AN XY: 727214

Gnomad4 AFR exome AF: 0.159

Gnomad4 AMR exome AF: 0.0171

Gnomad4 ASJ exome AF: 0.00310

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00926

Gnomad4 FIN exome AF: 0.0233

Gnomad4 NFE exome AF: 0.0116

Gnomad4 OTH exome AF: 0.0211

GnomAD4 genome AF: 0.0527 AC: 8013 AN: 152118 Hom.: 502 Cov.: 33 AF XY: 0.0515 AC XY: 3827 AN XY: 74372

Gnomad4 AFR AF: 0.153

Gnomad4 AMR AF: 0.0240

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00954

Gnomad4 FIN AF: 0.0241

Gnomad4 NFE AF: 0.0132

Gnomad4 OTH AF: 0.0436

Alfa AF: 0.0166 Hom.: 59

Bravo AF: 0.0568

TwinsUK AF: 0.0138 AC: 51

ALSPAC AF: 0.0127 AC: 49

ESP6500AA AF: 0.147 AC: 646

ESP6500EA AF: 0.0120 AC: 103

ExAC AF: 0.0241 AC: 2925

Asia WGS AF: 0.0120 AC: 43 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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	0.15
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.42	T;.;.;T;.
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.83	.;.;T;T;T
MetaRNN	Benign	0.0017	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M;M;M;M;M
MutationTaster	Benign	1.0	P;P;P;P;P;P;P;P
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-4.2	D;D;D;D;D
REVEL	Benign	0.16
Sift	Benign	0.047	D;D;D;D;D
Sift4G	Benign	0.087	T;T;T;T;T
Polyphen		0.98	D;D;D;D;D
Vest4		0.21
MPC		0.68
ClinPred		0.049	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.26
gMVP		0.76

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: rs3917991; hg19: chr1-36934805;