rs121913390

Positions:

• chr5-150073481-A-G
• chr5-150073481-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM5 PP5

The NM_001288705.3(CSF1R):​c.902T>C​(p.Leu301Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L301F) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CSF1R NM_001288705.3 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 4.18

Genes affected

CSF1R (HGNC:2433): (colony stimulating factor 1 receptor) The protein encoded by this gene is the receptor for colony stimulating factor 1, a cytokine which controls the production, differentiation, and function of macrophages. This receptor mediates most if not all of the biological effects of this cytokine. Ligand binding activates the receptor kinase through a process of oligomerization and transphosphorylation. The encoded protein is a tyrosine kinase transmembrane receptor and member of the CSF1/PDGF receptor family of tyrosine-protein kinases. Mutations in this gene have been associated with a predisposition to myeloid malignancy. The first intron of this gene contains a transcriptionally inactive ribosomal protein L7 processed pseudogene oriented in the opposite direction. Alternative splicing results in multiple transcript variants. Expression of a splice variant from an LTR promoter has been found in Hodgkin lymphoma (HL), HL cell lines and anaplastic large cell lymphoma. [provided by RefSeq, Mar 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-150073480-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376703.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP5: Variant 5-150073481-A-G is Pathogenic according to our data. Variant chr5-150073481-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376273.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CSF1R	NM_001288705.3	c.902T>C	p.Leu301Ser	missense_variant	6/21	ENST00000675795.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CSF1R	ENST00000675795.1	c.902T>C	p.Leu301Ser	missense_variant	6/21		NM_001288705.3	P1
CSF1R	ENST00000286301.7	c.902T>C	p.Leu301Ser	missense_variant	7/22	1		P1
CSF1R	ENST00000543093.1	c.890-2910T>C		intron_variant		1
CSF1R	ENST00000504875.5	c.902T>C	p.Leu301Ser	missense_variant, NMD_transcript_variant	6/20	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Neoplasm Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Jul 14, 2015

- -

Hematologic neoplasm Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 13, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D
Eigen	Benign	-0.092
Eigen_PC	Benign	-0.014
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.59	T
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Benign	-0.47	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	D;N
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.44
Sift	Benign	0.038	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.080	B
Vest4		0.66
MutPred		0.57		Gain of disorder (P = 0.0038);
MVP		0.67
MPC		0.32
ClinPred		0.84	D
GERP RS		4.8
Varity_R		0.91
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs121913390; hg19: chr5-149453044; COSMIC: COSV53842469; COSMIC: COSV53842469;