rs56960778

Positions:

• chrX-1305473-G-A
• chrX-1305473-G-C
• chrX-1305473-G-T

Variant summary

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

The ENST00000381500.6(CSF2RA):​c.974G>A​(p.Arg325His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000804 in 1,613,898 control chromosomes in the GnomAD database, including 5 homozygotes. There are 626 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R325C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0042 (2 hom., 306 hem., cov: 32)
  • Exomes 𝑓: 0.00045 (3 hom. 320 hem.)
• Consequence: CSF2RA ENST00000381500.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.45

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=0.004050523).
• BP6: Variant X-1305473-G-A is Benign according to our data. Variant chrX-1305473-G-A is described in ClinVar as [Benign]. Clinvar id is 537346.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 = 0.00416 (633/152232) while in subpopulation AFR AF= 0.0147 (612/41534). AF 95% confidence interval is 0.0138. There are 2 homozygotes in gnomad4. There are 306 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CSF2RA	NM_172245.4	c.1071G>A	p.Pro357=	synonymous_variant	12/13	ENST00000381529.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CSF2RA	ENST00000381529.9	c.1071G>A	p.Pro357=	synonymous_variant	12/13	1	NM_172245.4	A2

Frequencies

GnomAD3 genomes AF: 0.00415 AC: 631 AN: 152114 Hom.: 2 Cov.: 32 AF XY: 0.00410 AC XY: 305 AN XY: 74300

Gnomad AFR AF: 0.0147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000918

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00107 AC: 270 AN: 251168 Hom.: 1 AF XY: 0.000781 AC XY: 106 AN XY: 135738

Gnomad AFR exome AF: 0.0146

Gnomad AMR exome AF: 0.000809

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000454 AC: 664 AN: 1461666 Hom.: 3 Cov.: 32 AF XY: 0.000440 AC XY: 320 AN XY: 727142

Gnomad4 AFR exome AF: 0.0169

Gnomad4 AMR exome AF: 0.000783

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.000662

GnomAD4 genome AF: 0.00416 AC: 633 AN: 152232 Hom.: 2 Cov.: 32 AF XY: 0.00411 AC XY: 306 AN XY: 74428

Gnomad4 AFR AF: 0.0147

Gnomad4 AMR AF: 0.000916

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00190

Bravo AF: 0.00474

ESP6500AA AF: 0.0120 AC: 53

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00128 AC: 156

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Surfactant metabolism dysfunction, pulmonary, 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

CSF2RA-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 13, 2019

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	-0.30	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	0.18
DANN	Benign	0.35
FATHMM_MKL	Benign	0.0011	N
LIST_S2	Benign	0.32	T;T
MetaRNN	Benign	0.0041	T;T
MetaSVM	Benign	-0.29	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N
PROVEAN	Benign	0.12	N;N
REVEL	Benign	0.088
Sift	Benign	0.16	T;T
Sift4G	Benign	0.25	T;T
Polyphen		0.021	B;B
Vest4		0.22
MVP		0.41
ClinPred		0.0015	T
GERP RS		-0.43

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: rs56960778; hg19: chrX-1424366; COSMIC: COSV62626457; COSMIC: COSV62626457;