rs2229165

Variant names:

• chr1-109923933-G-A
• rs2229165
• NM_000757.6:c.1312G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000757.6(CSF1):​c.1312G>A​(p.Gly438Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0265 in 1,614,168 control chromosomes in the GnomAD database, including 2,236 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.059 (541 hom., cov: 34)
  • Exomes 𝑓: 0.023 (1695 hom.)
• Consequence: CSF1 NM_000757.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.447
• Publications: 18 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017989278).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.141 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSF1	NM_000757.6	c.1312G>A	p.Gly438Arg	missense_variant	Exon 6 of 9	ENST00000329608.11	NP_000748.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSF1	ENST00000329608.11	c.1312G>A	p.Gly438Arg	missense_variant	Exon 6 of 9	1	NM_000757.6	ENSP00000327513.6
CSF1	ENST00000369802.7	c.1312G>A	p.Gly438Arg	missense_variant	Exon 6 of 9	1		ENSP00000358817.3
CSF1	ENST00000369801.1	c.1091-127G>A		intron_variant	Intron 6 of 8	1		ENSP00000358816.1
CSF1	ENST00000420111.6	c.545-127G>A		intron_variant	Intron 5 of 8	5		ENSP00000407317.2

Frequencies

GnomAD3 genomes AF: 0.0591 AC: 8995 AN: 152224 Hom.: 537 Cov.: 34

Gnomad AFR AF: 0.141

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0754

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.150

Gnomad SAS AF: 0.0984

Gnomad FIN AF: 0.00706

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00725

Gnomad OTH AF: 0.0535

GnomAD2 exomes AF: 0.0496 AC: 12449 AN: 251096 AF XY: 0.0469

Gnomad AFR exome AF: 0.142

Gnomad AMR exome AF: 0.0919

Gnomad ASJ exome AF: 0.00726

Gnomad EAS exome AF: 0.158

Gnomad FIN exome AF: 0.00758

Gnomad NFE exome AF: 0.00696

Gnomad OTH exome AF: 0.0308

GnomAD4 exome AF: 0.0231 AC: 33825 AN: 1461826 Hom.: 1695 Cov.: 83 AF XY: 0.0244 AC XY: 17744 AN XY: 727216

African (AFR) AF: 0.148 AC: 4948 AN: 33480

American (AMR) AF: 0.0901 AC: 4031 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00719 AC: 188 AN: 26136

East Asian (EAS) AF: 0.168 AC: 6664 AN: 39700

South Asian (SAS) AF: 0.0920 AC: 7938 AN: 86256

European-Finnish (FIN) AF: 0.00818 AC: 437 AN: 53412

Middle Eastern (MID) AF: 0.0182 AC: 105 AN: 5766

European-Non Finnish (NFE) AF: 0.00678 AC: 7544 AN: 1111966

Other (OTH) AF: 0.0326 AC: 1970 AN: 60388

GnomAD4 genome AF: 0.0592 AC: 9021 AN: 152342 Hom.: 541 Cov.: 34 AF XY: 0.0607 AC XY: 4518 AN XY: 74488

African (AFR) AF: 0.142 AC: 5888 AN: 41572

American (AMR) AF: 0.0756 AC: 1157 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00778 AC: 27 AN: 3472

East Asian (EAS) AF: 0.150 AC: 777 AN: 5176

South Asian (SAS) AF: 0.0985 AC: 476 AN: 4834

European-Finnish (FIN) AF: 0.00706 AC: 75 AN: 10630

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.00723 AC: 492 AN: 68028

Other (OTH) AF: 0.0539 AC: 114 AN: 2114

Alfa AF: 0.0283 Hom.: 714

Bravo AF: 0.0685

TwinsUK AF: 0.00863 AC: 32

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.141 AC: 622

ESP6500EA AF: 0.00779 AC: 67

ExAC AF: 0.0502 AC: 6097

Asia WGS AF: 0.124 AC: 429 AN: 3478

EpiCase AF: 0.00725

EpiControl AF: 0.00605

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.0
DANN	Benign	0.55
DEOGEN2	Benign	0.24	T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.68	.;T
MetaRNN	Benign	0.0018	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.81	L;L
PhyloP100		-0.45
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.044
Sift	Benign	0.43	T;T
Sift4G	Benign	0.17	T;T
Polyphen		0.046	B;B
Vest4		0.058
MutPred		0.37		Gain of MoRF binding (P = 0.0214);Gain of MoRF binding (P = 0.0214);
MPC		0.14
ClinPred		0.00083	T
GERP RS		-3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.047
gMVP		0.12
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs2229165; hg19: chr1-110466555; COSMIC: COSV60034782; COSMIC: COSV60034782;