rs2229166

Variant names:

• chr1-109924188-C-T
• rs2229166
• NM_000757.6:c.1567C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-109924188-C-T
• chr1-109924188-C-A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_000757.6(CSF1):​c.1567C>T​(p.Arg523Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000483 in 1,602,274 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R523Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00050 (2 hom.)
• Consequence: CSF1 NM_000757.6 missense, splice_region
• Scores: Splicing: ADA: 0.4717
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.991
• Publications: 19 publications found

Genes affected

CSF1 (HGNC:2432): (colony stimulating factor 1) The protein encoded by this gene is a cytokine that controls the production, differentiation, and function of macrophages. The active form of the protein is found extracellularly as a disulfide-linked homodimer, and is thought to be produced by proteolytic cleavage of membrane-bound precursors. The encoded protein may be involved in development of the placenta. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2011]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12605402).
• BS2: High AC in GnomAd4 at 42 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000757.6. 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
	CSF1	NM_000757.6	MANE Select	c.1567C>T	p.Arg523Trp	missense splice_region	Exon 6 of 9	NP_000748.4
	CSF1	NM_172212.3		c.1567C>T	p.Arg523Trp	missense splice_region	Exon 6 of 9	NP_757351.2	P09603-1
	CSF1	NM_172210.3		c.1219C>T	p.Arg407Trp	missense splice_region	Exon 7 of 9	NP_757349.2	P09603-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSF1	ENST00000329608.11	TSL:1 MANE Select	c.1567C>T	p.Arg523Trp	missense splice_region	Exon 6 of 9	ENSP00000327513.6	P09603-1
	CSF1	ENST00000369802.7	TSL:1	c.1567C>T	p.Arg523Trp	missense splice_region	Exon 6 of 9	ENSP00000358817.3	P09603-1
	CSF1	ENST00000369801.1	TSL:1	c.1219C>T	p.Arg407Trp	missense splice_region	Exon 7 of 9	ENSP00000358816.1	P09603-2

Frequencies

GnomAD3 genomes AF: 0.000277 AC: 42 AN: 151880 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000234 AC: 55 AN: 235314 AF XY: 0.000242

Gnomad AFR exome AF: 0.0000666

Gnomad AMR exome AF: 0.0000905

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000398

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000505 AC: 732 AN: 1450276 Hom.: 2 Cov.: 36 AF XY: 0.000486 AC XY: 350 AN XY: 720710

African (AFR) AF: 0.0000903 AC: 3 AN: 33214

American (AMR) AF: 0.0000919 AC: 4 AN: 43524

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25106

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39622

South Asian (SAS) AF: 0.000189 AC: 16 AN: 84698

European-Finnish (FIN) AF: 0.0000382 AC: 2 AN: 52342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5650

European-Non Finnish (NFE) AF: 0.000614 AC: 679 AN: 1106310

Other (OTH) AF: 0.000435 AC: 26 AN: 59810

GnomAD4 genome AF: 0.000276 AC: 42 AN: 151998 Hom.: 0 Cov.: 31 AF XY: 0.000283 AC XY: 21 AN XY: 74276

African (AFR) AF: 0.000121 AC: 5 AN: 41428

American (AMR) AF: 0.0000655 AC: 1 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5144

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10560

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000500 AC: 34 AN: 67998

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.00000906 Hom.: 2128

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00130 AC: 5

ExAC AF: 0.000199 AC: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D
Eigen	Benign	-0.0024
Eigen_PC	Benign	0.073
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.86	D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.99
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.21
Sift	Benign	0.10	T
Sift4G	Benign	0.16	T
Polyphen		0.65	P
Vest4		0.45
MVP		0.62
MPC		0.40
ClinPred		0.15	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.069
gMVP		0.45
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.47
dbscSNV1_RF	Benign	0.40
SpliceAI score (max)		0.18		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: rs2229166; hg19: chr1-110466810;