rs2066934

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000504875.5(CSF1R):n.*776A>C 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 0.77 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
ENST00000504875.5 non_coding_transcript_exon

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.659

Publications

21 publications found

Variant links:

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

CSF1R links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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 link	c.*36A>C		3_prime_UTR_variant	Exon 21 of 21	ENST00000675795.1	NP_001275634.1	P07333-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSF1R	ENST00000675795.1 link	c.*36A>C		3_prime_UTR_variant	Exon 21 of 21		NM_001288705.3	ENSP00000501699.1		P07333-1

Frequencies

GnomAD3 genomes

AF:

0.816

AC:

123736

AN:

151584

Hom.:

51032

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.770

AC:

187786

AN:

243844

AF XY:

0.761

show subpopulations

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 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.:

AF XY:

0.761

AC XY:

550300

AN XY:

722792

show subpopulations

African (AFR)

AF:

0.953

AC:

31742

AN:

33320

American (AMR)

AF:

0.778

AC:

34392

AN:

44186

Ashkenazi Jewish (ASJ)

AF:

0.802

AC:

20875

AN:

26032

East Asian (EAS)

AF:

0.674

AC:

26603

AN:

39472

South Asian (SAS)

AF:

0.684

AC:

58317

AN:

85298

European-Finnish (FIN)

AF:

0.809

AC:

42896

AN:

53020

Middle Eastern (MID)

AF:

0.758

AC:

4324

AN:

5706

European-Non Finnish (NFE)

AF:

0.764

AC:

845258

AN:

1105944

Other (OTH)

AF:

0.776

AC:

46635

AN:

60076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

13863

27725

41588

55450

69313

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20322

40644

60966

81288

101610

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.816

AC:

123841

AN:

151706

Hom.:

51083

Cov.:

AF XY:

0.815

AC XY:

60410

AN XY:

74126

show subpopulations

African (AFR)

AF:

0.946

AC:

39189

AN:

41410

American (AMR)

AF:

0.784

AC:

11977

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.806

AC:

2794

AN:

3466

East Asian (EAS)

AF:

0.716

AC:

3664

AN:

5114

South Asian (SAS)

AF:

0.685

AC:

3292

AN:

4808

European-Finnish (FIN)

AF:

0.806

AC:

8494

AN:

10534

Middle Eastern (MID)

AF:

0.707

AC:

208

AN:

294

European-Non Finnish (NFE)

AF:

0.767

AC:

51989

AN:

67792

Other (OTH)

AF:

0.782

AC:

1650

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1119

2238

3357

4476

5595

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

866

1732

2598

3464

4330

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

LINK: link

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

(source)

DANN

Benign

0.23

PhyloP100

0.66

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over