chr5-150070569-T-C

Variant names:

• chr5-150070569-T-C
• rs10079250
• NM_001288705.3:c.1085A>G

Variant summary

Our verdict is Benign. The variant received -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. 13/21 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. H362Y) 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
• Publications: 68 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 (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 VariationId is 352157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
CSF1R	NM_001288705.3	c.1085A>G	p.His362Arg	missense_variant, splice_region_variant	Exon 7 of 21	ENST00000675795.1	NP_001275634.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSF1R	ENST00000675795.1	c.1085A>G	p.His362Arg	missense_variant, splice_region_variant	Exon 7 of 21		NM_001288705.3	ENSP00000501699.1
CSF1R	ENST00000286301.7	c.1085A>G	p.His362Arg	missense_variant, splice_region_variant	Exon 8 of 22	1		ENSP00000286301.3
CSF1R	ENST00000543093.1	c.892A>G	p.Thr298Ala	missense_variant, splice_region_variant	Exon 6 of 6	1		ENSP00000445282.1
CSF1R	ENST00000504875.5	n.1085A>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 7 of 20	1		ENSP00000422212.1

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

GnomAD2 exomes AF: 0.0989 AC: 12544 AN: 126780 AF XY: 0.101

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 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

African (AFR) AF: 0.111 AC: 3370 AN: 30292

American (AMR) AF: 0.0648 AC: 1954 AN: 30148

Ashkenazi Jewish (ASJ) AF: 0.0958 AC: 2206 AN: 23020

East Asian (EAS) AF: 0.317 AC: 11257 AN: 35508

South Asian (SAS) AF: 0.117 AC: 8601 AN: 73376

European-Finnish (FIN) AF: 0.0231 AC: 1119 AN: 48428

Middle Eastern (MID) AF: 0.120 AC: 662 AN: 5522

European-Non Finnish (NFE) AF: 0.0687 AC: 73260 AN: 1065758

Other (OTH) AF: 0.0934 AC: 5292 AN: 56670

GnomAD4 genome AF: 0.0888 AC: 13522 AN: 152220 Hom.: 878 Cov.: 32 AF XY: 0.0877 AC XY: 6526 AN XY: 74432

African (AFR) AF: 0.110 AC: 4577 AN: 41520

American (AMR) AF: 0.0762 AC: 1167 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0943 AC: 327 AN: 3468

East Asian (EAS) AF: 0.365 AC: 1882 AN: 5158

South Asian (SAS) AF: 0.117 AC: 565 AN: 4824

European-Finnish (FIN) AF: 0.0221 AC: 235 AN: 10618

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.0664 AC: 4516 AN: 68004

Other (OTH) AF: 0.0936 AC: 198 AN: 2116

Alfa AF: 0.0827 Hom.: 2197

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

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. -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 22, 2014

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 31182772, 30136118, 28724665, 25144241) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
PhyloP100		0.59
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
Mutation Taster		=93/7	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: rs10079250; hg19: chr5-149450132; COSMIC: COSV53840176; COSMIC: COSV53840176;