rs28722602

chrX-1309528-G-AchrX-1309528-G-T

Variant summary

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

The ENST00000355432.8(CSF2RA):c.1073G>A(p.Arg358Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0121 in 1,613,780 control chromosomes in the GnomAD database, including 195 homozygotes. There are 10,195 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R358L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0091 (9 hom., 703 hem., cov: 33)
  • Exomes 𝑓: 0.012 (186 hom. 9492 hem.)
• Consequence: CSF2RA ENST00000355432.8 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.816

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=0.0028986335).
• BP6: Variant X-1309528-G-A is Benign according to our data. Variant chrX-1309528-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3036043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00915 (1392/152192) while in subpopulation SAS AF= 0.0324 (156/4822). AF 95% confidence interval is 0.0282. There are 9 homozygotes in gnomad4. There are 703 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CSF2RA	NM_172245.4	c.*49G>A		3_prime_UTR_variant	13/13	ENST00000381529.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CSF2RA	ENST00000381529.9	c.*49G>A		3_prime_UTR_variant	13/13	1	NM_172245.4	A2

Frequencies

GnomAD3 genomes AF: 0.00916 AC: 1393 AN: 152074 Hom.: 9 Cov.: 33 AF XY: 0.00946 AC XY: 703 AN XY: 74292

Gnomad AFR AF: 0.00242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00936

Gnomad ASJ AF: 0.0135

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0325

Gnomad FIN AF: 0.0104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0120

Gnomad OTH AF: 0.00957

GnomAD3 exomes AF: 0.0116 AC: 2901 AN: 251160 Hom.: 36 AF XY: 0.0131 AC XY: 1778 AN XY: 135722

Gnomad AFR exome AF: 0.00197

Gnomad AMR exome AF: 0.00581

Gnomad ASJ exome AF: 0.0137

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0303

Gnomad FIN exome AF: 0.00924

Gnomad NFE exome AF: 0.0117

Gnomad OTH exome AF: 0.0114

GnomAD4 exome AF: 0.0124 AC: 18193 AN: 1461588 Hom.: 186 Cov.: 33 AF XY: 0.0131 AC XY: 9492 AN XY: 727078

Gnomad4 AFR exome AF: 0.00179

Gnomad4 AMR exome AF: 0.00749

Gnomad4 ASJ exome AF: 0.0135

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0302

Gnomad4 FIN exome AF: 0.0105

Gnomad4 NFE exome AF: 0.0122

Gnomad4 OTH exome AF: 0.0113

GnomAD4 genome AF: 0.00915 AC: 1392 AN: 152192 Hom.: 9 Cov.: 33 AF XY: 0.00945 AC XY: 703 AN XY: 74420

Gnomad4 AFR AF: 0.00241

Gnomad4 AMR AF: 0.00935

Gnomad4 ASJ AF: 0.0135

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0324

Gnomad4 FIN AF: 0.0104

Gnomad4 NFE AF: 0.0120

Gnomad4 OTH AF: 0.00947

TwinsUK AF: 0.0154 AC: 57

ALSPAC AF: 0.0135 AC: 52

ExAC AF: 0.0121 AC: 1475

EpiCase AF: 0.00987

EpiControl AF: 0.0113

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 01, 2022

p.Arg358Gln in exon 11 of CSF2RA: This variant is not expected to have clinical significance because it has been identified in 3% (927/30780) of South Asian chromosomes, including 17 homozygotes and 1.2% (1538/128868) of European chromosomes, including 13 homozygotes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1; BP4. -

CSF2RA-related disorder Benign:1

Likely benign, criteria provided, single submitter

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_addAF	Benign	-0.90	T
BayesDel_noAF	Benign	-1.1
Cadd	Benign	0.71
Dann	Benign	0.69
FATHMM_MKL	Benign	0.0017	N
LIST_S2	Benign	0.30	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N
PROVEAN	Benign	0.21	N
REVEL	Benign	0.019
Sift	Pathogenic	0.0	D
Vest4		0.12
ClinPred		0.0082	T
GERP RS		-0.69

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: rs28722602; hg19: chrX-1428421; COSMIC: COSV62624509; COSMIC: COSV62624509;