5-150053835-AG-AGGG

Variant names:

• chr5-150053835-A-AGG
• rs200927456
• NM_001288705.3:c.*232_*233dupCC

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001288705.3(CSF1R):​c.*232_*233dupCC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000020 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CSF1R NM_001288705.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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: Uncertain_significance. The variant received 0 ACMG points.

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.*232_*233dupCC		3_prime_UTR	Exon 21 of 21	NP_001275634.1	P07333-1
	CSF1R	NM_001349736.2		c.*232_*233dupCC		3_prime_UTR	Exon 23 of 23	NP_001336665.1	P07333-1
	CSF1R	NM_001375320.1		c.*232_*233dupCC		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.*232_*233dupCC		3_prime_UTR	Exon 21 of 21	ENSP00000501699.1	P07333-1
	CSF1R	ENST00000286301.7	TSL:1	c.*232_*233dupCC		3_prime_UTR	Exon 22 of 22	ENSP00000286301.3	P07333-1
	CSF1R	ENST00000504875.5	TSL:1	n.*972_*973dupCC		non_coding_transcript_exon	Exon 20 of 20	ENSP00000422212.1	E9PEK4

Frequencies

GnomAD3 genomes AF: 0.000277 AC: 27 AN: 97474 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.000864

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000860

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: 0.00

Gnomad OTH AF: 0.00142

GnomAD4 exome AF: 0.0000197 AC: 8 AN: 406350 Hom.: 0 Cov.: 4 AF XY: 0.0000141 AC XY: 3 AN XY: 213288

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

African (AFR) AF: 0.000319 AC: 3 AN: 9396

American (AMR) AF: 0.000176 AC: 3 AN: 17002

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12698

East Asian (EAS) AF: 0.00 AC: 0 AN: 28530

South Asian (SAS) AF: 0.00 AC: 0 AN: 41616

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26456

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1846

European-Non Finnish (NFE) AF: 0.00000408 AC: 1 AN: 245050

Other (OTH) AF: 0.0000421 AC: 1 AN: 23756

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00164431), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000277 AC: 27 AN: 97558 Hom.: 0 Cov.: 29 AF XY: 0.000275 AC XY: 13 AN XY: 47294

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

African (AFR) AF: 0.000861 AC: 24 AN: 27872

American (AMR) AF: 0.0000859 AC: 1 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: 0.00 AC: 0 AN: 41532

Other (OTH) AF: 0.00140 AC: 2 AN: 1432

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000664687), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary diffuse leukoencephalopathy with spheroids (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.15

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs200927456; hg19: chr5-149433398;