X-1309528-G-T

Position:

• chrX-1309528-G-T

Variant summary

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

The ENST00000355432.8(CSF2RA):​c.1073G>T​(p.Arg358Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0843 in 1,613,540 control chromosomes in the GnomAD database, including 10,306 homozygotes. There are 71,282 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. R358Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.14 (2542 hom., 10929 hem., cov: 33)
  • Exomes 𝑓: 0.078 (7764 hom. 60353 hem.)
• Consequence: CSF2RA ENST00000355432.8 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• 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=0.0031292737).
• BP6: Variant X-1309528-G-T is Benign according to our data. Variant chrX-1309528-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 226543.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.308 is higher than 0.05.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21955 AN: 152040 Hom.: 2527 Cov.: 33 AF XY: 0.147 AC XY: 10885 AN XY: 74270

Gnomad AFR AF: 0.312

Gnomad AMI AF: 0.0811

Gnomad AMR AF: 0.114

Gnomad ASJ AF: 0.0521

Gnomad EAS AF: 0.138

Gnomad SAS AF: 0.282

Gnomad FIN AF: 0.0787

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.0561

Gnomad OTH AF: 0.138

GnomAD3 exomes AF: 0.113 AC: 28443 AN: 251160 Hom.: 2628 AF XY: 0.116 AC XY: 15770 AN XY: 135722

Gnomad AFR exome AF: 0.315

Gnomad AMR exome AF: 0.0998

Gnomad ASJ exome AF: 0.0448

Gnomad EAS exome AF: 0.138

Gnomad SAS exome AF: 0.265

Gnomad FIN exome AF: 0.0711

Gnomad NFE exome AF: 0.0585

Gnomad OTH exome AF: 0.0964

GnomAD4 exome AF: 0.0780 AC: 113991 AN: 1461382 Hom.: 7764 Cov.: 33 AF XY: 0.0830 AC XY: 60353 AN XY: 726962

Gnomad4 AFR exome AF: 0.315

Gnomad4 AMR exome AF: 0.101

Gnomad4 ASJ exome AF: 0.0444

Gnomad4 EAS exome AF: 0.138

Gnomad4 SAS exome AF: 0.261

Gnomad4 FIN exome AF: 0.0679

Gnomad4 NFE exome AF: 0.0534

Gnomad4 OTH exome AF: 0.0982

GnomAD4 genome AF: 0.145 AC: 22006 AN: 152158 Hom.: 2542 Cov.: 33 AF XY: 0.147 AC XY: 10929 AN XY: 74398

Gnomad4 AFR AF: 0.312

Gnomad4 AMR AF: 0.114

Gnomad4 ASJ AF: 0.0521

Gnomad4 EAS AF: 0.138

Gnomad4 SAS AF: 0.282

Gnomad4 FIN AF: 0.0787

Gnomad4 NFE AF: 0.0561

Gnomad4 OTH AF: 0.138

Bravo AF: 0.149

TwinsUK AF: 0.0561 AC: 208

ALSPAC AF: 0.0503 AC: 194

ESP6500AA AF: 0.300 AC: 1324

ESP6500EA AF: 0.0556 AC: 478

ExAC AF: 0.120 AC: 14550

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

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

Nov 26, 2014

p.Arg358Leu in exon 11 of CSF2RA: This variant is not expected to have clinical significance because it has been identified in 30% (1324/4406) of African Americ an chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.e du/EVS/; dbSNP rs28722602). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 06, 2019

- -

CSF2RA-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 03, 2020

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	-0.99	T
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.59
DANN	Benign	0.13
FATHMM_MKL	Benign	0.00028	N
LIST_S2	Benign	0.24	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N
PROVEAN	Benign	2.1	N
REVEL	Benign	0.042
Sift	Pathogenic	0.0	D
Vest4		0.24
ClinPred		0.0024	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: COSV62623352; COSMIC: COSV62623352;