rs2066933

Variant names:

• chr5-150054034-G-A
• rs2066933
• ENST00000504875.5:n.*775C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-150054034-G-A
• chr5-150054034-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000504875.5(CSF1R):​n.*775C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.769 in 1,604,874 control chromosomes in the GnomAD database, including 477,231 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.82 (51049 hom., cov: 31)
  • Exomes 𝑓: 0.76 (426182 hom.)
• Consequence: CSF1R ENST00000504875.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.245
• Publications: 17 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 5-150054034-G-A is Benign according to our data. Variant chr5-150054034-G-A is described in ClinVar as Benign. ClinVar VariationId is 352121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.938 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSF1R	NM_001288705.3	c.*35C>T		3_prime_UTR_variant	Exon 21 of 21	ENST00000675795.1	NP_001275634.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSF1R	ENST00000675795.1	c.*35C>T		3_prime_UTR_variant	Exon 21 of 21		NM_001288705.3	ENSP00000501699.1

Frequencies

GnomAD3 genomes AF: 0.816 AC: 123688 AN: 151578 Hom.: 50998 Cov.: 31

Gnomad AFR AF: 0.946

Gnomad AMI AF: 0.647

Gnomad AMR AF: 0.784

Gnomad ASJ AF: 0.806

Gnomad EAS AF: 0.711

Gnomad SAS AF: 0.685

Gnomad FIN AF: 0.806

Gnomad MID AF: 0.723

Gnomad NFE AF: 0.767

Gnomad OTH AF: 0.785

GnomAD2 exomes AF: 0.769 AC: 188046 AN: 244396 AF XY: 0.760

Gnomad AFR exome AF: 0.950

Gnomad AMR exome AF: 0.778

Gnomad ASJ exome AF: 0.801

Gnomad EAS exome AF: 0.728

Gnomad FIN exome AF: 0.802

Gnomad NFE exome AF: 0.762

Gnomad OTH exome AF: 0.768

GnomAD4 exome AF: 0.764 AC: 1110901 AN: 1453174 Hom.: 426182 Cov.: 30 AF XY: 0.761 AC XY: 550281 AN XY: 722938

African (AFR) AF: 0.953 AC: 31740 AN: 33318

American (AMR) AF: 0.778 AC: 34418 AN: 44220

Ashkenazi Jewish (ASJ) AF: 0.802 AC: 20881 AN: 26040

East Asian (EAS) AF: 0.670 AC: 26447 AN: 39474

South Asian (SAS) AF: 0.684 AC: 58358 AN: 85360

European-Finnish (FIN) AF: 0.809 AC: 42927 AN: 53054

Middle Eastern (MID) AF: 0.757 AC: 4327 AN: 5718

European-Non Finnish (NFE) AF: 0.764 AC: 845177 AN: 1105912

Other (OTH) AF: 0.776 AC: 46626 AN: 60078

GnomAD4 genome AF: 0.816 AC: 123793 AN: 151700 Hom.: 51049 Cov.: 31 AF XY: 0.815 AC XY: 60384 AN XY: 74124

African (AFR) AF: 0.946 AC: 39182 AN: 41404

American (AMR) AF: 0.784 AC: 11978 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.806 AC: 2794 AN: 3466

East Asian (EAS) AF: 0.711 AC: 3633 AN: 5110

South Asian (SAS) AF: 0.685 AC: 3287 AN: 4800

European-Finnish (FIN) AF: 0.806 AC: 8496 AN: 10538

Middle Eastern (MID) AF: 0.707 AC: 208 AN: 294

European-Non Finnish (NFE) AF: 0.767 AC: 51981 AN: 67798

Other (OTH) AF: 0.782 AC: 1650 AN: 2110

Alfa AF: 0.792 Hom.: 27931

Bravo AF: 0.821

Asia WGS AF: 0.728 AC: 2535 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary diffuse leukoencephalopathy with spheroids Benign:2

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

May 10, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Brain abnormalities, neurodegeneration, and dysosteosclerosis Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.89
DANN	Benign	0.49
PhyloP100		0.24
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2066933; hg19: chr5-149433597;