5-150053835-AG-AGG

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_001288705.3(CSF1R):​c.*233dupC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00344 in 503,844 control chromosomes in the GnomAD database, including 26 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.012 (20 hom., cov: 29)
  • Exomes 𝑓: 0.0013 (6 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: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0125 (1217/97550) while in subpopulation AFR AF = 0.0407 (1135/27866). AF 95% confidence interval is 0.0388. There are 20 homozygotes in GnomAd4. There are 579 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 20 AD,AR gene

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.*233dupC		3_prime_UTR	Exon 21 of 21	NP_001275634.1	P07333-1
	CSF1R	NM_001349736.2		c.*233dupC		3_prime_UTR	Exon 23 of 23	NP_001336665.1	P07333-1
	CSF1R	NM_001375320.1		c.*233dupC		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.*233dupC		3_prime_UTR	Exon 21 of 21	ENSP00000501699.1	P07333-1
	CSF1R	ENST00000286301.7	TSL:1	c.*233dupC		3_prime_UTR	Exon 22 of 22	ENSP00000286301.3	P07333-1
	CSF1R	ENST00000504875.5	TSL:1	n.*973dupC		non_coding_transcript_exon	Exon 20 of 20	ENSP00000422212.1	E9PEK4

Frequencies

GnomAD3 genomes AF: 0.0124 AC: 1212 AN: 97466 Hom.: 20 Cov.: 29

Gnomad AFR AF: 0.0407

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.000960

Gnomad EAS AF: 0.000536

Gnomad SAS AF: 0.000327

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000361

Gnomad OTH AF: 0.0170

GnomAD4 exome AF: 0.00127 AC: 516 AN: 406294 Hom.: 6 Cov.: 4 AF XY: 0.00113 AC XY: 242 AN XY: 213256

African (AFR) AF: 0.0332 AC: 312 AN: 9394

American (AMR) AF: 0.00253 AC: 43 AN: 16996

Ashkenazi Jewish (ASJ) AF: 0.000788 AC: 10 AN: 12696

East Asian (EAS) AF: 0.000175 AC: 5 AN: 28530

South Asian (SAS) AF: 0.000288 AC: 12 AN: 41616

European-Finnish (FIN) AF: 0.000340 AC: 9 AN: 26436

Middle Eastern (MID) AF: 0.000542 AC: 1 AN: 1844

European-Non Finnish (NFE) AF: 0.000298 AC: 73 AN: 245030

Other (OTH) AF: 0.00215 AC: 51 AN: 23752

GnomAD4 genome AF: 0.0125 AC: 1217 AN: 97550 Hom.: 20 Cov.: 29 AF XY: 0.0122 AC XY: 579 AN XY: 47290

African (AFR) AF: 0.0407 AC: 1135 AN: 27866

American (AMR) AF: 0.00326 AC: 38 AN: 11648

Ashkenazi Jewish (ASJ) AF: 0.000960 AC: 2 AN: 2084

East Asian (EAS) AF: 0.000537 AC: 2 AN: 3724

South Asian (SAS) AF: 0.000328 AC: 1 AN: 3046

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: 0.000361 AC: 15 AN: 41532

Other (OTH) AF: 0.0168 AC: 24 AN: 1432

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.15
Mutation Taster		=100/0	polymorphism

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;