5-150066358-T-C

Variant names:

• chr5-150066358-T-C
• rs216146
• NM_001288705.3:c.1626+1857A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001288705.3(CSF1R):​c.1626+1857A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.56 in 152,042 control chromosomes in the GnomAD database, including 24,103 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.56 (24103 hom., cov: 32)
• Consequence: CSF1R NM_001288705.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.294
• Publications: 8 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.587 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001288705.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSF1R	NM_001288705.3	MANE Select	c.1626+1857A>G		intron	N/A	NP_001275634.1
	CSF1R	NM_001349736.2		c.1626+1857A>G		intron	N/A	NP_001336665.1
	CSF1R	NM_001375320.1		c.1626+1857A>G		intron	N/A	NP_001362249.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSF1R	ENST00000675795.1	MANE Select	c.1626+1857A>G		intron	N/A	ENSP00000501699.1
	CSF1R	ENST00000286301.7	TSL:1	c.1626+1857A>G		intron	N/A	ENSP00000286301.3
	CSF1R	ENST00000504875.5	TSL:1	n.1626+1857A>G		intron	N/A	ENSP00000422212.1

Frequencies

GnomAD3 genomes AF: 0.560 AC: 85043 AN: 151924 Hom.: 24098 Cov.: 32

Gnomad AFR AF: 0.513

Gnomad AMI AF: 0.533

Gnomad AMR AF: 0.486

Gnomad ASJ AF: 0.511

Gnomad EAS AF: 0.492

Gnomad SAS AF: 0.570

Gnomad FIN AF: 0.702

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.592

Gnomad OTH AF: 0.510

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.560 AC: 85082 AN: 152042 Hom.: 24103 Cov.: 32 AF XY: 0.564 AC XY: 41924 AN XY: 74334

African (AFR) AF: 0.513 AC: 21262 AN: 41466

American (AMR) AF: 0.486 AC: 7428 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.511 AC: 1771 AN: 3468

East Asian (EAS) AF: 0.493 AC: 2539 AN: 5154

South Asian (SAS) AF: 0.570 AC: 2749 AN: 4824

European-Finnish (FIN) AF: 0.702 AC: 7419 AN: 10574

Middle Eastern (MID) AF: 0.479 AC: 140 AN: 292

European-Non Finnish (NFE) AF: 0.592 AC: 40221 AN: 67970

Other (OTH) AF: 0.507 AC: 1068 AN: 2106

Alfa AF: 0.556 Hom.: 29636

Bravo AF: 0.540

Asia WGS AF: 0.473 AC: 1648 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.4
DANN	Benign	0.80
PhyloP100		0.29
Mutation Taster		=100/0	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: rs216146; hg19: chr5-149445921; COSMIC: COSV53831628; COSMIC: COSV53831628;