5-150053300-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001288705.3(CSF1R):c.*769A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.155 in 232,418 control chromosomes in the GnomAD database, including 3,217 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.16 (2275 hom., cov: 32)
  • Exomes 𝑓: 0.15 (942 hom.)
• Consequence: CSF1R NM_001288705.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.27

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 5-150053300-T-C is Benign according to our data. Variant chr5-150053300-T-C is described in ClinVar as [Benign]. Clinvar id is 352100.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.28 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CSF1R	NM_001288705.3	c.*769A>G		3_prime_UTR_variant	21/21	ENST00000675795.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CSF1R	ENST00000675795.1	c.*769A>G		3_prime_UTR_variant	21/21		NM_001288705.3	P1
CSF1R	ENST00000286301.7	c.*769A>G		3_prime_UTR_variant	22/22	1		P1
CSF1R	ENST00000504875.5	c.*1509A>G		3_prime_UTR_variant, NMD_transcript_variant	20/20	1

Frequencies

GnomAD3 genomes AF: 0.160 AC: 24302 AN: 152034 Hom.: 2279 Cov.: 32

Gnomad AFR AF: 0.210

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.287

Gnomad ASJ AF: 0.177

Gnomad EAS AF: 0.146

Gnomad SAS AF: 0.0506

Gnomad FIN AF: 0.0878

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.119

Gnomad OTH AF: 0.184

GnomAD4 exome AF: 0.147 AC: 11835 AN: 80266 Hom.: 942 Cov.: 0 AF XY: 0.148 AC XY: 5457 AN XY: 36984

Gnomad4 AFR exome AF: 0.214

Gnomad4 AMR exome AF: 0.299

Gnomad4 ASJ exome AF: 0.177

Gnomad4 EAS exome AF: 0.164

Gnomad4 SAS exome AF: 0.0501

Gnomad4 FIN exome AF: 0.106

Gnomad4 NFE exome AF: 0.128

Gnomad4 OTH exome AF: 0.155

GnomAD4 genome AF: 0.160 AC: 24298 AN: 152152 Hom.: 2275 Cov.: 32 AF XY: 0.159 AC XY: 11809 AN XY: 74402

Gnomad4 AFR AF: 0.210

Gnomad4 AMR AF: 0.287

Gnomad4 ASJ AF: 0.177

Gnomad4 EAS AF: 0.146

Gnomad4 SAS AF: 0.0496

Gnomad4 FIN AF: 0.0878

Gnomad4 NFE AF: 0.119

Gnomad4 OTH AF: 0.181

Alfa AF: 0.134 Hom.: 2174

Bravo AF: 0.183

Asia WGS AF: 0.110 AC: 385 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary diffuse leukoencephalopathy with spheroids Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
Cadd	Benign	13
Dann	Benign	0.71

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

Publications

LitVar

Other links and lift over

dbSNP: rs3828609; hg19: chr5-149432863; COSMIC: COSV53841175; COSMIC: COSV53841175;