Genetic Variant CSF1R:p.Cys653Tyr (chr5-150060873-C-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001288705.3(CSF1R):c.1958G>A(p.Cys653Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C653R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CSF1R
NM_001288705.3 missense

Scores

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: 7.84

Publications

6 publications found

Variant links:

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]

CSF1R Gene-Disease associations (from GenCC):

hereditary diffuse leukoencephalopathy with axonal spheroids and pigmented glia
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Orphanet
brain abnormalities, neurodegeneration, and dysosteosclerosis
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
leukoencephalopathy, diffuse hereditary, with spheroids 1
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
early-onset calcifying leukoencephalopathy-skeletal dysplasia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CSF1R links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.991

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSF1R	NM_001288705.3 link	c.1958G>A	p.Cys653Tyr	missense_variant	Exon 13 of 21	ENST00000675795.1	NP_001275634.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSF1R	ENST00000675795.1 link	c.1958G>A	p.Cys653Tyr	missense_variant	Exon 13 of 21		NM_001288705.3	ENSP00000501699.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1456032

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723606

African (AFR)

AF:

0.00

AC:

AN:

33424

American (AMR)

AF:

0.00

AC:

AN:

44130

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25968

East Asian (EAS)

AF:

0.00

AC:

AN:

39602

South Asian (SAS)

AF:

0.00

AC:

AN:

84726

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53074

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109140

Other (OTH)

AF:

0.00

AC:

AN:

60206

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

LINK: link

Submissions by phenotype

Hereditary diffuse leukoencephalopathy with spheroids

Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.80

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.44

MetaRNN

Pathogenic

0.99

MetaSVM

Uncertain

0.51

MutationAssessor

Benign

1.1

PhyloP100

7.8

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-9.5

REVEL

Pathogenic

0.84

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0090

Polyphen

1.0

Vest4

0.98

MutPred

0.92

Gain of sheet (P = 0.0827);

MVP

0.95

MPC

1.1

ClinPred

1.0

GERP RS

4.8

Varity_R

0.96

gMVP

0.97

Mutation Taster

=12/88

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over