chr5-150056214-C-T

Variant names:

• chr5-150056214-C-T
• NM_001288705.3:c.2442+5G>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_001288705.3(CSF1R):​c.2442+5G>A variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CSF1R NM_001288705.3 splice_region, intron
• Scores: Splicing: ADA: 0.9991
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 7.55

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 5-150056214-C-T is Pathogenic according to our data. Variant chr5-150056214-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1331662.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSF1R	NM_001288705.3	c.2442+5G>A		splice_region_variant, intron_variant	Intron 17 of 20	ENST00000675795.1	NP_001275634.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSF1R	ENST00000675795.1	c.2442+5G>A		splice_region_variant, intron_variant	Intron 17 of 20		NM_001288705.3	ENSP00000501699.1
CSF1R	ENST00000286301.7	c.2442+5G>A		splice_region_variant, intron_variant	Intron 18 of 21	1		ENSP00000286301.3
CSF1R	ENST00000504875.5	n.*263+5G>A		splice_region_variant, intron_variant	Intron 16 of 19	1		ENSP00000422212.1
CSF1R	ENST00000515068.1	n.*416+5G>A		splice_region_variant, intron_variant	Intron 6 of 6	5		ENSP00000427545.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Oct 23, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 18 of the CSF1R gene. It does not directly change the encoded amino acid sequence of the CSF1R protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of CSF1R-related conditions (PMID: 27680516). ClinVar contains an entry for this variant (Variation ID: 1331662). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the c.2442+5G nucleotide in the CSF1R gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 22197934). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Jan 25, 2021

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS4_Supporting, PP3, PM2 -

Inborn genetic diseases Pathogenic:1

Jun 18, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The 2442+5G>A intronic alteration results from a G to A substitution 5 nucleotides after exon 18 (coding exon 17) of the CSF1R gene. for autosomal dominant CSF1R-related diffuse leukoencephalopathy with spheroids; however, its clinical significance for autosomal recessive CSF1R-related brain abnormalities, neurodegeneration, and dysosteosclerosis is uncertain This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been detected in one individual in a large cohort of individuals with adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (Konno, 2017). This nucleotide position is highly conserved in available vertebrate species. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Based on the available evidence, this alteration is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	25
DANN	Benign	0.88

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-149435777;