5-150053557-A-G

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.*512T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0808 in 243,734 control chromosomes in the GnomAD database, including 1,210 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.089 (853 hom., cov: 32)
  • Exomes 𝑓: 0.068 (357 hom.)
• Consequence: CSF1R NM_001288705.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.474

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=-0.87).
• BP6: Variant 5-150053557-A-G is Benign according to our data. Variant chr5-150053557-A-G is described in ClinVar as [Benign]. Clinvar id is 352107.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.181 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CSF1R	NM_001288705.3	c.*512T>C		3_prime_UTR_variant	21/21	ENST00000675795.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CSF1R	ENST00000675795.1	c.*512T>C		3_prime_UTR_variant	21/21		NM_001288705.3	P1
CSF1R	ENST00000286301.7	c.*512T>C		3_prime_UTR_variant	22/22	1		P1
CSF1R	ENST00000504875.5	c.*1252T>C		3_prime_UTR_variant, NMD_transcript_variant	20/20	1

Frequencies

GnomAD3 genomes AF: 0.0886 AC: 13451 AN: 151798 Hom.: 849 Cov.: 32

Gnomad AFR AF: 0.181

Gnomad AMI AF: 0.0406

Gnomad AMR AF: 0.0523

Gnomad ASJ AF: 0.0418

Gnomad EAS AF: 0.192

Gnomad SAS AF: 0.0580

Gnomad FIN AF: 0.0455

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0457

Gnomad OTH AF: 0.0739

GnomAD4 exome AF: 0.0677 AC: 6214 AN: 91818 Hom.: 357 Cov.: 0 AF XY: 0.0656 AC XY: 2804 AN XY: 42756

Gnomad4 AFR exome AF: 0.188

Gnomad4 AMR exome AF: 0.0454

Gnomad4 ASJ exome AF: 0.0404

Gnomad4 EAS exome AF: 0.177

Gnomad4 SAS exome AF: 0.0633

Gnomad4 FIN exome AF: 0.0465

Gnomad4 NFE exome AF: 0.0416

Gnomad4 OTH exome AF: 0.0694

GnomAD4 genome AF: 0.0887 AC: 13475 AN: 151916 Hom.: 853 Cov.: 32 AF XY: 0.0881 AC XY: 6538 AN XY: 74242

Gnomad4 AFR AF: 0.181

Gnomad4 AMR AF: 0.0521

Gnomad4 ASJ AF: 0.0418

Gnomad4 EAS AF: 0.191

Gnomad4 SAS AF: 0.0576

Gnomad4 FIN AF: 0.0455

Gnomad4 NFE AF: 0.0457

Gnomad4 OTH AF: 0.0745

Alfa AF: 0.0616 Hom.: 160

Bravo AF: 0.0947

Asia WGS AF: 0.136 AC: 471 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	-0.87
Cadd	Benign	5.2
Dann	Benign	0.68

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: rs13117; hg19: chr5-149433120;