rs2228422

Variant names:

• chr5-150078115-G-A
• rs2228422
• NM_001288705.3:c.726C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-150078115-G-A
• chr5-150078115-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001288705.3(CSF1R):​c.726C>T​(p.Thr242Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.537 in 1,613,634 control chromosomes in the GnomAD database, including 239,809 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (18805 hom., cov: 31)
  • Exomes 𝑓: 0.54 (221004 hom.)
• Consequence: CSF1R NM_001288705.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0320
• Publications: 31 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: Orphanet, Genomics England PanelApp, Ambry Genetics
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 5-150078115-G-A is Benign according to our data. Variant chr5-150078115-G-A is described in ClinVar as Benign. ClinVar VariationId is 352165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.032 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.563 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSF1R	NM_001288705.3	MANE Select	c.726C>T	p.Thr242Thr	synonymous	Exon 4 of 21	NP_001275634.1	P07333-1
	CSF1R	NM_001349736.2		c.726C>T	p.Thr242Thr	synonymous	Exon 6 of 23	NP_001336665.1	P07333-1
	CSF1R	NM_001375320.1		c.726C>T	p.Thr242Thr	synonymous	Exon 6 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.726C>T	p.Thr242Thr	synonymous	Exon 4 of 21	ENSP00000501699.1	P07333-1
	CSF1R	ENST00000286301.7	TSL:1	c.726C>T	p.Thr242Thr	synonymous	Exon 5 of 22	ENSP00000286301.3	P07333-1
	CSF1R	ENST00000543093.1	TSL:1	c.726C>T	p.Thr242Thr	synonymous	Exon 4 of 6	ENSP00000445282.1	P07333-2

Frequencies

GnomAD3 genomes AF: 0.479 AC: 72739 AN: 151820 Hom.: 18804 Cov.: 31

Gnomad AFR AF: 0.322

Gnomad AMI AF: 0.485

Gnomad AMR AF: 0.424

Gnomad ASJ AF: 0.495

Gnomad EAS AF: 0.218

Gnomad SAS AF: 0.552

Gnomad FIN AF: 0.706

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.567

Gnomad OTH AF: 0.439

GnomAD2 exomes AF: 0.510 AC: 128270 AN: 251364 AF XY: 0.519

Gnomad AFR exome AF: 0.320

Gnomad AMR exome AF: 0.416

Gnomad ASJ exome AF: 0.488

Gnomad EAS exome AF: 0.219

Gnomad FIN exome AF: 0.697

Gnomad NFE exome AF: 0.568

Gnomad OTH exome AF: 0.516

GnomAD4 exome AF: 0.543 AC: 794223 AN: 1461696 Hom.: 221004 Cov.: 55 AF XY: 0.545 AC XY: 396352 AN XY: 727176

African (AFR) AF: 0.319 AC: 10686 AN: 33476

American (AMR) AF: 0.415 AC: 18534 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.491 AC: 12820 AN: 26124

East Asian (EAS) AF: 0.216 AC: 8585 AN: 39700

South Asian (SAS) AF: 0.552 AC: 47637 AN: 86248

European-Finnish (FIN) AF: 0.695 AC: 37124 AN: 53416

Middle Eastern (MID) AF: 0.425 AC: 2453 AN: 5766

European-Non Finnish (NFE) AF: 0.562 AC: 625297 AN: 1111870

Other (OTH) AF: 0.515 AC: 31087 AN: 60384

GnomAD4 genome AF: 0.479 AC: 72767 AN: 151938 Hom.: 18805 Cov.: 31 AF XY: 0.485 AC XY: 36054 AN XY: 74276

African (AFR) AF: 0.321 AC: 13313 AN: 41432

American (AMR) AF: 0.424 AC: 6478 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.495 AC: 1720 AN: 3472

East Asian (EAS) AF: 0.219 AC: 1127 AN: 5148

South Asian (SAS) AF: 0.553 AC: 2661 AN: 4816

European-Finnish (FIN) AF: 0.706 AC: 7466 AN: 10574

Middle Eastern (MID) AF: 0.391 AC: 115 AN: 294

European-Non Finnish (NFE) AF: 0.567 AC: 38526 AN: 67900

Other (OTH) AF: 0.437 AC: 923 AN: 2112

Alfa AF: 0.519 Hom.: 33258

Bravo AF: 0.447

Asia WGS AF: 0.414 AC: 1439 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Hereditary diffuse leukoencephalopathy with spheroids (4)
-	-	1	Brain abnormalities, neurodegeneration, and dysosteosclerosis (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	5.3
DANN	Benign	0.39
PhyloP100		0.032
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs2228422; hg19: chr5-149457678; COSMIC: COSV53827656; COSMIC: COSV53827656;