rs3828609

Variant names:

• chr5-150053300-T-C
• rs3828609
• ENST00000504875.5:n.*1509A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000504875.5(CSF1R):​n.*1509A>G variant causes a non coding transcript exon 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 ENST00000504875.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.27
• Publications: 12 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]

HMGXB3 (HGNC:28982): (HMG-box containing 3) This gene is one of the non-canonical high mobility group (HMG) genes. The encoded protein contains an HMG-box domain found in DNA binding proteins such as transcription factors and chromosomal proteins. [provided by RefSeq, Aug 2011]

HMGXB3 Gene-Disease associations (from GenCC):

• Tourette syndrome

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
CSF1R	NM_001288705.3	c.*769A>G		3_prime_UTR_variant	Exon 21 of 21	ENST00000675795.1	NP_001275634.1
HMGXB3	NM_014983.3	c.*1108T>C		downstream_gene_variant		ENST00000502717.6	NP_055798.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSF1R	ENST00000675795.1	c.*769A>G		3_prime_UTR_variant	Exon 21 of 21		NM_001288705.3	ENSP00000501699.1
HMGXB3	ENST00000502717.6	c.*1108T>C		downstream_gene_variant		1	NM_014983.3	ENSP00000421917.1

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

African (AFR) AF: 0.214 AC: 814 AN: 3796

American (AMR) AF: 0.299 AC: 733 AN: 2452

Ashkenazi Jewish (ASJ) AF: 0.177 AC: 889 AN: 5036

East Asian (EAS) AF: 0.164 AC: 1853 AN: 11272

South Asian (SAS) AF: 0.0501 AC: 35 AN: 698

European-Finnish (FIN) AF: 0.106 AC: 52 AN: 492

Middle Eastern (MID) AF: 0.215 AC: 105 AN: 488

European-Non Finnish (NFE) AF: 0.128 AC: 6318 AN: 49346

Other (OTH) AF: 0.155 AC: 1036 AN: 6686

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

African (AFR) AF: 0.210 AC: 8693 AN: 41486

American (AMR) AF: 0.287 AC: 4387 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.177 AC: 614 AN: 3468

East Asian (EAS) AF: 0.146 AC: 754 AN: 5176

South Asian (SAS) AF: 0.0496 AC: 239 AN: 4816

European-Finnish (FIN) AF: 0.0878 AC: 930 AN: 10588

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.119 AC: 8112 AN: 67998

Other (OTH) AF: 0.181 AC: 383 AN: 2114

Alfa AF: 0.134 Hom.: 4974

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		2.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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