1-36472668-A-G

Position:

• chr1-36472668-A-G

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.692T>C​(p.Met231Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00535 in 1,602,134 control chromosomes in the GnomAD database, including 241 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M231I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.024 (120 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (121 hom.)
• Consequence: CSF3R NM_000760.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0300

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]

CSF3R (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025488436).
• BP6: Variant 1-36472668-A-G is Benign according to our data. Variant chr1-36472668-A-G is described in ClinVar as [Benign]. Clinvar id is 256794.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0774 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CSF3R	NM_000760.4	c.692T>C	p.Met231Thr	missense_variant	7/17	ENST00000373106.6	NP_000751.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CSF3R	ENST00000373106.6	c.692T>C	p.Met231Thr	missense_variant	7/17	1	NM_000760.4	ENSP00000362198.2

Frequencies

GnomAD3 genomes AF: 0.0241 AC: 3670 AN: 152186 Hom.: 119 Cov.: 32

Gnomad AFR AF: 0.0796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0132

Gnomad ASJ AF: 0.00980

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00137

Gnomad OTH AF: 0.0192

GnomAD3 exomes AF: 0.00670 AC: 1605 AN: 239628 Hom.: 44 AF XY: 0.00549 AC XY: 719 AN XY: 130890

Gnomad AFR exome AF: 0.0794

Gnomad AMR exome AF: 0.00516

Gnomad ASJ exome AF: 0.0114

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000200

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00127

Gnomad OTH exome AF: 0.00620

GnomAD4 exome AF: 0.00337 AC: 4889 AN: 1449830 Hom.: 121 Cov.: 32 AF XY: 0.00312 AC XY: 2245 AN XY: 719372

Gnomad4 AFR exome AF: 0.0840

Gnomad4 AMR exome AF: 0.00557

Gnomad4 ASJ exome AF: 0.0123

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.000234

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000965

Gnomad4 OTH exome AF: 0.00687

GnomAD4 genome AF: 0.0242 AC: 3682 AN: 152304 Hom.: 120 Cov.: 32 AF XY: 0.0235 AC XY: 1753 AN XY: 74474

Gnomad4 AFR AF: 0.0797

Gnomad4 AMR AF: 0.0131

Gnomad4 ASJ AF: 0.00980

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00137

Gnomad4 OTH AF: 0.0190

Alfa AF: 0.00538 Hom.: 41

Bravo AF: 0.0279

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0649 AC: 283

ESP6500EA AF: 0.00164 AC: 14

ExAC AF: 0.00758 AC: 918

Asia WGS AF: 0.00289 AC: 10 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	0.057
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.15
DANN	Benign	0.22
DEOGEN2	Benign	0.070	T;.;.;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0018	N
LIST_S2	Benign	0.30	.;.;T;T;T
MetaRNN	Benign	0.0025	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.1	N;N;N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.27	N;N;N;N;N
REVEL	Benign	0.064
Sift	Benign	0.80	T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.0	B;B;B;B;B
Vest4		0.016
MVP		0.44
MPC		0.33
ClinPred		0.00077	T
GERP RS		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3917973; hg19: chr1-36938269;