rs10079250

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001288705.3(CSF1R):c.1085A>G(p.His362Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0797 in 1,520,942 control chromosomes in the GnomAD database, including 6,662 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.089 ( 878 hom., cov: 32)

Exomes 𝑓: 0.079 ( 5784 hom. )

Consequence

CSF1R
NM_001288705.3 missense, splice_region

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.587

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004469186).

BP6

Variant 5-150070569-T-C is Benign according to our data. Variant chr5-150070569-T-C is described in ClinVar as [Benign]. Clinvar id is 352157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-150070569-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.351 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CSF1R	NM_001288705.3 linkuse as main transcript	c.1085A>G	p.His362Arg	missense_variant, splice_region_variant	7/21	ENST00000675795.1	NP_001275634.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CSF1R	ENST00000675795.1 linkuse as main transcript	c.1085A>G	p.His362Arg	missense_variant, splice_region_variant	7/21		NM_001288705.3	ENSP00000501699	P1	P07333-1
CSF1R	ENST00000286301.7 linkuse as main transcript	c.1085A>G	p.His362Arg	missense_variant, splice_region_variant	8/22	1		ENSP00000286301	P1	P07333-1
CSF1R	ENST00000543093.1 linkuse as main transcript	c.892A>G	p.Thr298Ala	missense_variant, splice_region_variant	6/6	1		ENSP00000445282		P07333-2
CSF1R	ENST00000504875.5 linkuse as main transcript	c.1085A>G	p.His362Arg	missense_variant, splice_region_variant, NMD_transcript_variant	7/20	1		ENSP00000422212

Frequencies

GnomAD3 genomes

AF:

0.0889

AC:

13519

AN:

152102

Hom.:

880

Cov.:

show subpopulations

Gnomad AFR

AF:

0.110

Gnomad AMI

AF:

0.0186

Gnomad AMR

AF:

0.0763

Gnomad ASJ

AF:

0.0943

Gnomad EAS

AF:

0.365

Gnomad SAS

AF:

0.118

Gnomad FIN

AF:

0.0221

Gnomad MID

AF:

0.133

Gnomad NFE

AF:

0.0664

Gnomad OTH

AF:

0.0931

GnomAD3 exomes

AF:

0.0989

AC:

12544

AN:

126780

Hom.:

1133

AF XY:

0.101

AC XY:

6567

AN XY:

65256

show subpopulations

Gnomad AFR exome

AF:

0.104

Gnomad AMR exome

AF:

0.0645

Gnomad ASJ exome

AF:

0.0983

Gnomad EAS exome

AF:

0.389

Gnomad SAS exome

AF:

0.117

Gnomad FIN exome

AF:

0.0213

Gnomad NFE exome

AF:

0.0700

Gnomad OTH exome

AF:

0.101

GnomAD4 exome

AF:

0.0787

AC:

107721

AN:

1368722

Hom.:

5784

Cov.:

AF XY:

0.0797

AC XY:

53671

AN XY:

673046

show subpopulations

Gnomad4 AFR exome

AF:

0.111

Gnomad4 AMR exome

AF:

0.0648

Gnomad4 ASJ exome

AF:

0.0958

Gnomad4 EAS exome

AF:

0.317

Gnomad4 SAS exome

AF:

0.117

Gnomad4 FIN exome

AF:

0.0231

Gnomad4 NFE exome

AF:

0.0687

Gnomad4 OTH exome

AF:

0.0934

GnomAD4 genome

AF:

0.0888

AC:

13522

AN:

152220

Hom.:

878

Cov.:

AF XY:

0.0877

AC XY:

6526

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.110

Gnomad4 AMR

AF:

0.0762

Gnomad4 ASJ

AF:

0.0943

Gnomad4 EAS

AF:

0.365

Gnomad4 SAS

AF:

0.117

Gnomad4 FIN

AF:

0.0221

Gnomad4 NFE

AF:

0.0664

Gnomad4 OTH

AF:

0.0936

Alfa

AF:

0.0817

Hom.:

1561

Bravo

AF:

0.0952

TwinsUK

AF:

0.0734

AC:

272

ALSPAC

AF:

0.0727

AC:

280

ESP6500AA

AF:

0.0968

AC:

414

ESP6500EA

AF:

0.0619

AC:

516

ExAC

AF:

0.0489

AC:

4499

Asia WGS

AF:

0.170

AC:

589

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary diffuse leukoencephalopathy with spheroids

Benign:3

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Dec 22, 2014	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	This variant is associated with the following publications: (PMID: 31182772, 30136118, 28724665, 25144241) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.67

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.52

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.075

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.65

MetaRNN

Benign

0.0045

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.34

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-3.4

REVEL

Benign

0.084

Sift

Benign

0.061

Sift4G

Benign

0.14

Polyphen

0.26

Vest4

0.18

MPC

0.31

ClinPred

0.025

GERP RS

4.4

Varity_R

0.20

gMVP

0.74

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over