rs2228422

chr5-150078115-G-Achr5-150078115-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001288705.3(CSF1R):c.726C>T(p.Thr242=) 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

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 352165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-150078115-G-A is described in Lovd as [Benign].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CSF1R	NM_001288705.3	c.726C>T	p.Thr242=	synonymous_variant	4/21	ENST00000675795.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CSF1R	ENST00000675795.1	c.726C>T	p.Thr242=	synonymous_variant	4/21		NM_001288705.3	P1

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

GnomAD3 exomes AF: 0.510 AC: 128270 AN: 251364 Hom.: 34743 AF XY: 0.519 AC XY: 70554 AN XY: 135844

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 SAS exome AF: 0.555

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

Gnomad4 AFR exome AF: 0.319

Gnomad4 AMR exome AF: 0.415

Gnomad4 ASJ exome AF: 0.491

Gnomad4 EAS exome AF: 0.216

Gnomad4 SAS exome AF: 0.552

Gnomad4 FIN exome AF: 0.695

Gnomad4 NFE exome AF: 0.562

Gnomad4 OTH exome AF: 0.515

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

Gnomad4 AFR AF: 0.321

Gnomad4 AMR AF: 0.424

Gnomad4 ASJ AF: 0.495

Gnomad4 EAS AF: 0.219

Gnomad4 SAS AF: 0.553

Gnomad4 FIN AF: 0.706

Gnomad4 NFE AF: 0.567

Gnomad4 OTH AF: 0.437

Alfa AF: 0.526 Hom.: 27453

Bravo AF: 0.447

Asia WGS AF: 0.414 AC: 1439 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary diffuse leukoencephalopathy with spheroids Benign:4

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Jan 09, 2015	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Brain abnormalities, neurodegeneration, and dysosteosclerosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
Cadd	Benign	5.3
Dann	Benign	0.39

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

Publications

LitVar

Other links and lift over

dbSNP: rs2228422; hg19: chr5-149457678; COSMIC: COSV53827656; COSMIC: COSV53827656;