chrX-1309488-G-A

Variant names:

• chrX-1309488-G-A
• rs2229236
• ENST00000355432.8:c.1033G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_172246.4(CSF2RA):​c.1033G>A​(p.Gly345Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0151 in 1,613,916 control chromosomes in the GnomAD database, including 3,001 homozygotes. There are 10,907 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 10/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.079 (1581 hom., 5644 hem., cov: 33)
  • Exomes 𝑓: 0.0085 (1420 hom. 5263 hem.)
• Consequence: CSF2RA NM_172246.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.02

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 (MetaRNN=0.006300956).
• BP6: Variant X-1309488-G-A is Benign according to our data. Variant chrX-1309488-G-A is described in ClinVar as [Benign]. Clinvar id is 178719.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.269 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSF2RA	NM_172245.4	c.*9G>A		3_prime_UTR_variant	Exon 13 of 13	ENST00000381529.9	NP_758448.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSF2RA	ENST00000381529.9	c.*9G>A		3_prime_UTR_variant	Exon 13 of 13	1	NM_172245.4	ENSP00000370940.3

Frequencies

GnomAD3 genomes AF: 0.0783 AC: 11919 AN: 152156 Hom.: 1573 Cov.: 33 AF XY: 0.0755 AC XY: 5613 AN XY: 74338

Gnomad AFR AF: 0.273

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0251

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.00126

Gnomad OTH AF: 0.0455

GnomAD3 exomes AF: 0.0206 AC: 5179 AN: 251182 Hom.: 611 AF XY: 0.0149 AC XY: 2021 AN XY: 135744

Gnomad AFR exome AF: 0.273

Gnomad AMR exome AF: 0.0124

Gnomad ASJ exome AF: 0.0102

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000686

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00110

Gnomad OTH exome AF: 0.00897

GnomAD4 exome AF: 0.00849 AC: 12408 AN: 1461642 Hom.: 1420 Cov.: 32 AF XY: 0.00724 AC XY: 5263 AN XY: 727130

Gnomad4 AFR exome AF: 0.283

Gnomad4 AMR exome AF: 0.0141

Gnomad4 ASJ exome AF: 0.00930

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000730

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.000696

Gnomad4 OTH exome AF: 0.0183

GnomAD4 genome AF: 0.0785 AC: 11954 AN: 152274 Hom.: 1581 Cov.: 33 AF XY: 0.0758 AC XY: 5644 AN XY: 74466

Gnomad4 AFR AF: 0.273

Gnomad4 AMR AF: 0.0249

Gnomad4 ASJ AF: 0.00893

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00126

Gnomad4 OTH AF: 0.0450

Bravo AF: 0.0897

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.272 AC: 1198

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.0255 AC: 3100

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jan 13, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

*9G>A in exon 14 of CSF2RA: This variant is not expected to have clinical signif icance because it has been identified in 27.2% (1198/4406) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs141486727). -

Surfactant metabolism dysfunction, pulmonary, 4 Benign:1

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CSF2RA-related disorder Benign:1

Jun 13, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as 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_addAF	Benign	-0.93	T
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.0050
DANN	Uncertain	0.99
FATHMM_MKL	Benign	0.0024	N
LIST_S2	Benign	0.34	T
MetaRNN	Benign	0.0063	T
MetaSVM	Benign	-1.0	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.028
Sift	Pathogenic	0.0	D
Vest4		0.13
ClinPred		0.0076	T
GERP RS		-0.99

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: rs2229236; hg19: chrX-1428381;