17-40015720-C-G

Variant names:

• chr17-40015720-C-G
• rs141490008
• NM_172219.3:c.70C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_172219.3(CSF3):​c.70C>G​(p.Leu24Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,443,256 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L24F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CSF3 NM_172219.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.709
• Publications: 0 publications found

Genes affected

CSF3 (HGNC:2438): (colony stimulating factor 3) This gene encodes a member of the IL-6 superfamily of cytokines. The encoded cytokine controls the production, differentiation, and function of granulocytes. Granulocytes are a type of white blood cell that are part of the innate immune response. A modified form of this protein is commonly administered to manage chemotherapy-induced neutropenia. Alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, May 2020]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31728983).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_172219.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSF3	NM_172219.3	MANE Select	c.70C>G	p.Leu24Val	missense	Exon 2 of 5	NP_757373.1	Q6FH65
	CSF3	NM_000759.4		c.70C>G	p.Leu24Val	missense	Exon 2 of 5	NP_000750.1	P09919-1
	CSF3	NM_172220.3		c.70C>G	p.Leu24Val	missense	Exon 2 of 4	NP_757374.2	P09919-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSF3	ENST00000394149.8	TSL:1 MANE Select	c.70C>G	p.Leu24Val	missense	Exon 2 of 5	ENSP00000377705.4	P09919-2
	CSF3	ENST00000225474.6	TSL:1	c.70C>G	p.Leu24Val	missense	Exon 2 of 5	ENSP00000225474.2	P09919-1
	CSF3	ENST00000331769.6	TSL:1	c.58C>G	p.Leu20Val	missense	Exon 1 of 4	ENSP00000327766.2	Q8N4W3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1443256 Hom.: 0 Cov.: 33 AF XY: 0.00000140 AC XY: 1 AN XY: 716178

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33192

American (AMR) AF: 0.00 AC: 0 AN: 42432

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25672

East Asian (EAS) AF: 0.00 AC: 0 AN: 39102

South Asian (SAS) AF: 0.0000120 AC: 1 AN: 83598

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52026

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5100

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1102564

Other (OTH) AF: 0.00 AC: 0 AN: 59570

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.71
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.032
Sift	Benign	0.084	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.26
MutPred		0.43		Loss of stability (P = 0.034)
MVP		0.46
MPC		0.68
ClinPred		0.44	T
GERP RS		3.1
PromoterAI		0.011	Neutral
Varity_R		0.076
gMVP		0.30
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs141490008; hg19: chr17-38171973;