1-109911058-C-T

Variant names:

• chr1-109911058-C-T
• rs987277680
• NM_000757.6:c.35C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000757.6(CSF1):​c.35C>T​(p.Pro12Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000104 in 958,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. P12R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000010 (0 hom.)
• Consequence: CSF1 NM_000757.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.09
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19357634).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSF1	NM_000757.6	c.35C>T	p.Pro12Leu	missense_variant	Exon 1 of 9	ENST00000329608.11	NP_000748.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSF1	ENST00000329608.11	c.35C>T	p.Pro12Leu	missense_variant	Exon 1 of 9	1	NM_000757.6	ENSP00000327513.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000104 AC: 1 AN: 958752 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 453234

African (AFR) AF: 0.00 AC: 0 AN: 18608

American (AMR) AF: 0.00 AC: 0 AN: 6080

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9302

East Asian (EAS) AF: 0.00 AC: 0 AN: 12958

South Asian (SAS) AF: 0.00 AC: 0 AN: 20352

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 11670

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2270

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 842786

Other (OTH) AF: 0.00 AC: 0 AN: 34726

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	.;T;T;T;.;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.68	T;.;T;T;T;T
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.19	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	.;L;.;L;L;L
PhyloP100		1.1
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.0	N;N;N;N;N;N
REVEL	Benign	0.054
Sift	Benign	0.12	T;D;T;D;D;D
Sift4G	Benign	0.13	T;T;D;T;T;T
Polyphen		0.61, 0.0030, 0.19	.;P;.;P;B;B
Vest4		0.13, 0.11, 0.10, 0.13
MutPred		0.57		Loss of glycosylation at P12 (P = 0.0234);Loss of glycosylation at P12 (P = 0.0234);Loss of glycosylation at P12 (P = 0.0234);Loss of glycosylation at P12 (P = 0.0234);Loss of glycosylation at P12 (P = 0.0234);Loss of glycosylation at P12 (P = 0.0234);
MVP		0.28
MPC		0.42
ClinPred		0.37	T
GERP RS		2.9
PromoterAI		0.062	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.092
gMVP		0.35
Mutation Taster		=92/8	polymorphism

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: rs987277680; hg19: chr1-110453680;