1-109923844-T-C

Variant names:

• chr1-109923844-T-C
• rs1058885
• NM_000757.6:c.1223T>C

Variant summary

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

The NM_000757.6(CSF1):​c.1223T>C​(p.Leu408Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.375 in 1,613,608 control chromosomes in the GnomAD database, including 116,041 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 0.39 (11701 hom., cov: 33)
  • Exomes 𝑓: 0.37 (104340 hom.)
• Consequence: CSF1 NM_000757.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.34
• Publications: 43 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=4.0016703E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.578 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSF1	NM_000757.6	c.1223T>C	p.Leu408Pro	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.1223T>C	p.Leu408Pro	missense_variant	Exon 6 of 9	1	NM_000757.6	ENSP00000327513.6

Frequencies

GnomAD3 genomes AF: 0.388 AC: 58903 AN: 151914 Hom.: 11688 Cov.: 33

Gnomad AFR AF: 0.433

Gnomad AMI AF: 0.401

Gnomad AMR AF: 0.356

Gnomad ASJ AF: 0.447

Gnomad EAS AF: 0.597

Gnomad SAS AF: 0.365

Gnomad FIN AF: 0.269

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.369

Gnomad OTH AF: 0.377

GnomAD2 exomes AF: 0.376 AC: 94103 AN: 250576 AF XY: 0.375

Gnomad AFR exome AF: 0.428

Gnomad AMR exome AF: 0.330

Gnomad ASJ exome AF: 0.443

Gnomad EAS exome AF: 0.584

Gnomad FIN exome AF: 0.274

Gnomad NFE exome AF: 0.365

Gnomad OTH exome AF: 0.376

GnomAD4 exome AF: 0.374 AC: 546809 AN: 1461576 Hom.: 104340 Cov.: 78 AF XY: 0.374 AC XY: 271591 AN XY: 727068

African (AFR) AF: 0.425 AC: 14235 AN: 33474

American (AMR) AF: 0.332 AC: 14816 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.446 AC: 11656 AN: 26114

East Asian (EAS) AF: 0.604 AC: 23962 AN: 39698

South Asian (SAS) AF: 0.361 AC: 31138 AN: 86204

European-Finnish (FIN) AF: 0.286 AC: 15278 AN: 53402

Middle Eastern (MID) AF: 0.357 AC: 2059 AN: 5768

European-Non Finnish (NFE) AF: 0.369 AC: 410702 AN: 1111868

Other (OTH) AF: 0.380 AC: 22963 AN: 60378

GnomAD4 genome AF: 0.388 AC: 58945 AN: 152032 Hom.: 11701 Cov.: 33 AF XY: 0.386 AC XY: 28656 AN XY: 74310

African (AFR) AF: 0.433 AC: 17967 AN: 41468

American (AMR) AF: 0.356 AC: 5441 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.447 AC: 1550 AN: 3466

East Asian (EAS) AF: 0.596 AC: 3056 AN: 5130

South Asian (SAS) AF: 0.366 AC: 1766 AN: 4820

European-Finnish (FIN) AF: 0.269 AC: 2844 AN: 10580

Middle Eastern (MID) AF: 0.388 AC: 114 AN: 294

European-Non Finnish (NFE) AF: 0.369 AC: 25050 AN: 67958

Other (OTH) AF: 0.375 AC: 791 AN: 2112

Alfa AF: 0.380 Hom.: 25714

Bravo AF: 0.396

TwinsUK AF: 0.392 AC: 1454

ALSPAC AF: 0.381 AC: 1468

ESP6500AA AF: 0.440 AC: 1940

ESP6500EA AF: 0.373 AC: 3204

ExAC AF: 0.380 AC: 46176

Asia WGS AF: 0.460 AC: 1598 AN: 3478

EpiCase AF: 0.368

EpiControl AF: 0.361

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.86	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.067
DANN	Benign	0.32
DEOGEN2	Benign	0.11	T;T
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.089	N
LIST_S2	Benign	0.20	.;T
MetaRNN	Benign	0.0000040	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.63	N;N
PhyloP100		-2.3
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.050	N;N
REVEL	Benign	0.010
Sift	Benign	0.20	T;T
Sift4G	Benign	0.14	T;T
Polyphen		0.0020	B;B
Vest4		0.027
MPC		0.18
ClinPred		0.025	T
GERP RS		-9.1
Varity_R		0.026
gMVP		0.21
Mutation Taster		=98/2	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: rs1058885; hg19: chr1-110466466; COSMIC: COSV60034687; COSMIC: COSV60034687;