rs587777247

chr5-150056319-G-Achr5-150056319-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001288705.3(CSF1R):c.2342C>T(p.Ala781Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A781E) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CSF1R NM_001288705.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 10.0

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 Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_001288705.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-150056319-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 120324.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.996
• PP5: Variant 5-150056319-G-A is Pathogenic according to our data. Variant chr5-150056319-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 162118.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CSF1R	NM_001288705.3	c.2342C>T	p.Ala781Val	missense_variant	17/21	ENST00000675795.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CSF1R	ENST00000675795.1	c.2342C>T	p.Ala781Val	missense_variant	17/21		NM_001288705.3	P1
CSF1R	ENST00000286301.7	c.2342C>T	p.Ala781Val	missense_variant	18/22	1		P1
CSF1R	ENST00000504875.5	c.*163C>T		3_prime_UTR_variant, NMD_transcript_variant	16/20	1
CSF1R	ENST00000515068.1	c.*316C>T		3_prime_UTR_variant, NMD_transcript_variant	6/7	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461892 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary diffuse leukoencephalopathy with spheroids Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 08, 2013	This variant has been previously reported as disease-causing and was found once in our laboratory in a 42-year-old female with progressive neurologic decline, upper motor neuron pathology, and diffuse demyelinating lesions in the brain. Father was similarly affected (not tested). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 17, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala781 amino acid residue in CSF1R. Other variant(s) that disrupt this residue have been observed in individuals with CSF1R-related conditions (PMID: 24336230), which suggests that this may be a clinically significant amino acid residue. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CSF1R protein function. ClinVar contains an entry for this variant (Variation ID: 162118). This missense change has been observed in individuals with clinical features of hereditary diffuse leukoencephalopathy with spheroids (PMID: 23816250, 24198292, 25563800; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 781 of the CSF1R protein (p.Ala781Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.012	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.95		Loss of sheet (P = 0.302);
MVP		0.98
MPC		2.9
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.98
gMVP		0.91

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: rs587777247; hg19: chr5-149435882; COSMIC: COSV53828067; COSMIC: COSV53828067;