rs10079250

Positions:

• chr5-150070569-T-C
• chr5-150070569-T-G

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.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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H362C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.089 (878 hom., cov: 32)
  • Exomes 𝑓: 0.079 (5784 hom.)
• Consequence: CSF1R NM_001288705.3 missense, splice_region
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.587

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 (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	UniProt
CSF1R	NM_001288705.3	c.1085A>G	p.His362Arg	missense_variant, splice_region_variant	7/21	ENST00000675795.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CSF1R	ENST00000675795.1	c.1085A>G	p.His362Arg	missense_variant, splice_region_variant	7/21		NM_001288705.3	P1
CSF1R	ENST00000286301.7	c.1085A>G	p.His362Arg	missense_variant, splice_region_variant	8/22	1		P1
CSF1R	ENST00000543093.1	c.892A>G	p.Thr298Ala	missense_variant, splice_region_variant	6/6	1
CSF1R	ENST00000504875.5	c.1085A>G	p.His362Arg	missense_variant, splice_region_variant, NMD_transcript_variant	7/20	1

Frequencies

GnomAD3 genomes AF: 0.0889 AC: 13519 AN: 152102 Hom.: 880 Cov.: 32

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

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.: 32 AF XY: 0.0797 AC XY: 53671 AN XY: 673046

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.: 32 AF XY: 0.0877 AC XY: 6526 AN XY: 74432

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

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.075
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.65	T
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.084
Sift	Benign	0.061	T
Sift4G	Benign	0.14	T
Polyphen		0.26	B
Vest4		0.18
MPC		0.31
ClinPred		0.025	T
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

Other links and lift over

dbSNP: rs10079250; hg19: chr5-149450132; COSMIC: COSV53840176; COSMIC: COSV53840176;