rs917027829

Positions:

• chr5-150069942-G-A
• chr5-150069942-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001288705.3(CSF1R):​c.1441C>T​(p.Gln481Ter) variant causes a stop gained change involving the alteration of a non-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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CSF1R NM_001288705.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: -0.180

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.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-150069942-G-A is Pathogenic according to our data. Variant chr5-150069942-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 520697.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.1441C>T	p.Gln481Ter	stop_gained	9/21	ENST00000675795.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CSF1R	ENST00000675795.1	c.1441C>T	p.Gln481Ter	stop_gained	9/21		NM_001288705.3	P1
CSF1R	ENST00000286301.7	c.1441C>T	p.Gln481Ter	stop_gained	10/22	1		P1
CSF1R	ENST00000504875.5	c.1441C>T	p.Gln481Ter	stop_gained, NMD_transcript_variant	9/20	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 18, 2023	This variant is demonstrated to induce nonsense-mediated decay and result in loss of function (Guo et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30982609) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 22, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 520697). This premature translational stop signal has been observed in individuals with autosomal dominant CSF1R-related conditions (Invitae). This variant has been reported in individual(s) with autosomal recessive brain abnormalities, neurodegeneration, and dysosteosclerosis (PMID: 30982609); however, the role of the variant in this condition is currently unclear. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln481*) in the CSF1R gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CSF1R are known to be pathogenic (PMID: 24336230, 24120500, 24145216). -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2015

- -

Hereditary diffuse leukoencephalopathy with spheroids Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

DASA

Mar 05, 2022

The c.1441C>T;p.(Gln481*) variant creates a premature translational stop signal in the CSF1R gene. It is expected to result in an absent or disrupted protein product - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 520697) - PS4. This variant is not present in population databases (rs917027829- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. In summary, the currently available evidence indicates that the variant is pathogenic. -

Brain abnormalities, neurodegeneration, and dysosteosclerosis Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 21, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	27
DANN	Benign	0.94
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.019	N
MutationTaster	Benign	1.0	A
Vest4		0.51
GERP RS		-1.1

Splicing

Name	Calibrated prediction	Score	Prediction
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

LitVar

Other links and lift over

dbSNP: rs917027829; hg19: chr5-149449505;