rs189869234

Positions:

• chrX-1294321-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_172245.4(CSF2RA):​c.647-7G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000528 in 1,613,114 control chromosomes in the GnomAD database, including 1 homozygotes. There are 390 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., 132 hem., cov: 32)
  • Exomes 𝑓: 0.00040 (1 hom. 258 hem.)
• Consequence: CSF2RA NM_172245.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001630
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.88

Genes affected

CSF2RA (HGNC:2435): (colony stimulating factor 2 receptor subunit alpha) The protein encoded by this gene is the alpha subunit of the heterodimeric receptor for colony stimulating factor 2, a cytokine which controls the production, differentiation, and function of granulocytes and macrophages. The encoded protein is a member of the cytokine family of receptors. This gene is found in the pseudoautosomal region (PAR) of the X and Y chromosomes. Multiple transcript variants encoding different isoforms have been found for this gene, with some of the isoforms being membrane-bound and others being soluble. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant X-1294321-G-A is Benign according to our data. Variant chrX-1294321-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 227280.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00178 (271/152208) while in subpopulation AFR AF= 0.00578 (240/41546). AF 95% confidence interval is 0.00518. There are 0 homozygotes in gnomad4. There are 132 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 132 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CSF2RA	NM_172245.4	c.647-7G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000381529.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CSF2RA	ENST00000381529.9	c.647-7G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_172245.4	A2

Frequencies

GnomAD3 genomes AF: 0.00179 AC: 272 AN: 152090 Hom.: 0 Cov.: 32 AF XY: 0.00179 AC XY: 133 AN XY: 74280

Gnomad AFR AF: 0.00582

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000788 AC: 198 AN: 251178 Hom.: 2 AF XY: 0.000670 AC XY: 91 AN XY: 135744

Gnomad AFR exome AF: 0.00720

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00427

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000397 AC: 580 AN: 1460906 Hom.: 1 Cov.: 32 AF XY: 0.000355 AC XY: 258 AN XY: 726766

Gnomad4 AFR exome AF: 0.00649

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.00402

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000156

Gnomad4 OTH exome AF: 0.000895

GnomAD4 genome AF: 0.00178 AC: 271 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.00177 AC XY: 132 AN XY: 74408

Gnomad4 AFR AF: 0.00578

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00189

Bravo AF: 0.00202

EpiCase AF: 0.000218

EpiControl AF: 0.000356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 16, 2015

c.647-7G>A in intron 8 of CSF2RA: This variant is not expected to have clinical significance because it has been identified in 0.7% (80/10406) of African chromo somes, including 1 homozygote by the Exome Aggregation Consortium (ExAC, http:// exac.broadinstitute.org; dbSNP rs189869234). -

Surfactant metabolism dysfunction, pulmonary, 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

CSF2RA-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 10, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.031
DANN	Benign	0.78

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000016
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.21		Position offset: 26

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs189869234; hg19: chrX-1413214; COSMIC: COSV62624807; COSMIC: COSV62624807;