rs2066934

Variant names:

• chr5-150054033-T-G
• rs2066934
• NM_001288705.3:c.*36A>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001288705.3(CSF1R):​c.*36A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.77 in 1,604,760 control chromosomes in the GnomAD database, including 477,374 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.82 (51083 hom., cov: 31)
  • Exomes 𝑓: 0.76 (426291 hom.)
• Consequence: CSF1R NM_001288705.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.659

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 5-150054033-T-G is Benign according to our data. Variant chr5-150054033-T-G is described in ClinVar as [Benign]. Clinvar id is 352120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.939 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSF1R	NM_001288705.3	c.*36A>C		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	c.*36A>C		3_prime_UTR_variant	Exon 21 of 21		NM_001288705.3	ENSP00000501699.1

Frequencies

GnomAD3 genomes AF: 0.816 AC: 123736 AN: 151584 Hom.: 51032 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: 0.717

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

GnomAD3 exomes AF: 0.770 AC: 187786 AN: 243844 Hom.: 72716 AF XY: 0.761 AC XY: 100367 AN XY: 131870

Gnomad AFR exome AF: 0.950

Gnomad AMR exome AF: 0.779

Gnomad ASJ exome AF: 0.800

Gnomad EAS exome AF: 0.735

Gnomad SAS exome AF: 0.683

Gnomad FIN exome AF: 0.802

Gnomad NFE exome AF: 0.762

Gnomad OTH exome AF: 0.769

GnomAD4 exome AF: 0.765 AC: 1111042 AN: 1453054 Hom.: 426291 Cov.: 30 AF XY: 0.761 AC XY: 550300 AN XY: 722792

Gnomad4 AFR exome AF: 0.953

Gnomad4 AMR exome AF: 0.778

Gnomad4 ASJ exome AF: 0.802

Gnomad4 EAS exome AF: 0.674

Gnomad4 SAS exome AF: 0.684

Gnomad4 FIN exome AF: 0.809

Gnomad4 NFE exome AF: 0.764

Gnomad4 OTH exome AF: 0.776

GnomAD4 genome AF: 0.816 AC: 123841 AN: 151706 Hom.: 51083 Cov.: 31 AF XY: 0.815 AC XY: 60410 AN XY: 74126

Gnomad4 AFR AF: 0.946

Gnomad4 AMR AF: 0.784

Gnomad4 ASJ AF: 0.806

Gnomad4 EAS AF: 0.716

Gnomad4 SAS AF: 0.685

Gnomad4 FIN AF: 0.806

Gnomad4 NFE AF: 0.767

Gnomad4 OTH AF: 0.782

Alfa AF: 0.785 Hom.: 12382

Bravo AF: 0.821

Asia WGS AF: 0.730 AC: 2540 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

Jan 12, 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. -

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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	-0.92
CADD	Benign	4.3
DANN	Benign	0.23

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: rs2066934; hg19: chr5-149433596; COSMIC: COSV53831508; COSMIC: COSV53831508;