1-109923844-T-C

Position:

• chr1-109923844-T-C

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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

Verdict is Benign. Variant got -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/exons	MANE	UniProt
CSF1	NM_000757.6	c.1223T>C	p.Leu408Pro	missense_variant	6/9	ENST00000329608.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CSF1	ENST00000329608.11	c.1223T>C	p.Leu408Pro	missense_variant	6/9	1	NM_000757.6	P4
CSF1	ENST00000369802.7	c.1223T>C	p.Leu408Pro	missense_variant	6/9	1		P4
CSF1	ENST00000369801.1	c.1090+133T>C		intron_variant		1
CSF1	ENST00000420111.6	c.545-216T>C		intron_variant		5		A1

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

GnomAD3 exomes AF: 0.376 AC: 94103 AN: 250576 Hom.: 18370 AF XY: 0.375 AC XY: 50877 AN XY: 135580

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 SAS exome AF: 0.361

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

Gnomad4 AFR exome AF: 0.425

Gnomad4 AMR exome AF: 0.332

Gnomad4 ASJ exome AF: 0.446

Gnomad4 EAS exome AF: 0.604

Gnomad4 SAS exome AF: 0.361

Gnomad4 FIN exome AF: 0.286

Gnomad4 NFE exome AF: 0.369

Gnomad4 OTH exome AF: 0.380

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

Gnomad4 AFR AF: 0.433

Gnomad4 AMR AF: 0.356

Gnomad4 ASJ AF: 0.447

Gnomad4 EAS AF: 0.596

Gnomad4 SAS AF: 0.366

Gnomad4 FIN AF: 0.269

Gnomad4 NFE AF: 0.369

Gnomad4 OTH AF: 0.375

Alfa AF: 0.380 Hom.: 17845

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
MetaRNN	Benign	0.0000040	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.63	N;N
MutationTaster	Benign	1.0	P;P;P;P;P
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1058885; hg19: chr1-110466466; COSMIC: COSV60034687; COSMIC: COSV60034687;