NM_001288705.3:c.*233delC

Variant names:

• chr5-150053835-AG-A
• rs200927456
• NM_001288705.3:c.*233delC

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_001288705.3(CSF1R):​c.*233delC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000149 in 503,390 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 29)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: CSF1R NM_001288705.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.152
• Publications: 0 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: Genomics England PanelApp, Ambry Genetics, Orphanet
• brain abnormalities, neurodegeneration, and dysosteosclerosis

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• 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: Likely_benign. The variant received -4 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000113 (11/97560) while in subpopulation AFR AF = 0.000359 (10/27874). AF 95% confidence interval is 0.000194. There are 0 homozygotes in GnomAd4. There are 7 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSF1R	NM_001288705.3	MANE Select	c.*233delC		3_prime_UTR	Exon 21 of 21	NP_001275634.1	P07333-1
	CSF1R	NM_001349736.2		c.*233delC		3_prime_UTR	Exon 23 of 23	NP_001336665.1	P07333-1
	CSF1R	NM_001375320.1		c.*233delC		3_prime_UTR	Exon 23 of 23	NP_001362249.1	P07333-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSF1R	ENST00000675795.1	MANE Select	c.*233delC		3_prime_UTR	Exon 21 of 21	ENSP00000501699.1	P07333-1
	CSF1R	ENST00000286301.7	TSL:1	c.*233delC		3_prime_UTR	Exon 22 of 22	ENSP00000286301.3	P07333-1
	CSF1R	ENST00000504875.5	TSL:1	n.*973delC		non_coding_transcript_exon	Exon 20 of 20	ENSP00000422212.1	E9PEK4

Frequencies

GnomAD3 genomes AF: 0.000113 AC: 11 AN: 97476 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.000360

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000241

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000158 AC: 64 AN: 405830 Hom.: 0 Cov.: 4 AF XY: 0.000160 AC XY: 34 AN XY: 213026

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000107 AC: 1 AN: 9378

American (AMR) AF: 0.000236 AC: 4 AN: 16968

Ashkenazi Jewish (ASJ) AF: 0.0000789 AC: 1 AN: 12682

East Asian (EAS) AF: 0.000211 AC: 6 AN: 28478

South Asian (SAS) AF: 0.000120 AC: 5 AN: 41586

European-Finnish (FIN) AF: 0.000227 AC: 6 AN: 26424

Middle Eastern (MID) AF: 0.000542 AC: 1 AN: 1846

European-Non Finnish (NFE) AF: 0.000143 AC: 35 AN: 244736

Other (OTH) AF: 0.000211 AC: 5 AN: 23732

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000113 AC: 11 AN: 97560 Hom.: 0 Cov.: 29 AF XY: 0.000148 AC XY: 7 AN XY: 47294

African (AFR) AF: 0.000359 AC: 10 AN: 27874

American (AMR) AF: 0.00 AC: 0 AN: 11648

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2084

East Asian (EAS) AF: 0.00 AC: 0 AN: 3724

South Asian (SAS) AF: 0.00 AC: 0 AN: 3048

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5290

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.0000241 AC: 1 AN: 41532

Other (OTH) AF: 0.00 AC: 0 AN: 1432

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000453

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.15

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: rs200927456; hg19: chr5-149433398;