rs150743648

Positions:

chrX-1285892-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The ENST00000381529.9(CSF2RA):c.191A>G(p.Asp64Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000501 in 1,613,860 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 384 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00056 ( 0 hom., 36 hem., cov: 31)

Exomes 𝑓: 0.00049 ( 0 hom. 348 hem. )

Consequence

CSF2RA
ENST00000381529.9 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3B:1O:1

Conservation

PhyloP100: 0.0610

Variant links:

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]

CSF2RA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010257632).

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000559 (85/152192) while in subpopulation AMR AF= 0.00183 (28/15262). AF 95% confidence interval is 0.0013. There are 0 homozygotes in gnomad4. There are 36 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Hemizygotes in GnomAd4 at 36 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CSF2RA	NM_172245.4 linkuse as main transcript	c.191A>G	p.Asp64Gly	missense_variant	4/13	ENST00000381529.9	NP_758448.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CSF2RA	ENST00000381529.9 linkuse as main transcript	c.191A>G	p.Asp64Gly	missense_variant	4/13	1	NM_172245.4	ENSP00000370940	A2	P15509-1

Frequencies

GnomAD3 genomes

AF:

0.000559

AC:

AN:

152074

Hom.:

Cov.:

AF XY:

0.000485

AC XY:

AN XY:

74296

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.00184

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000647

Gnomad OTH

AF:

0.000958

GnomAD3 exomes

AF:

0.000545

AC:

137

AN:

251176

Hom.:

AF XY:

0.000560

AC XY:

AN XY:

135742

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00173

Gnomad ASJ exome

AF:

0.000595

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000555

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.000495

AC:

723

AN:

1461668

Hom.:

Cov.:

AF XY:

0.000479

AC XY:

348

AN XY:

727142

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00154

Gnomad4 ASJ exome

AF:

0.000421

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000559

Gnomad4 OTH exome

AF:

0.000282

GnomAD4 genome

AF:

0.000559

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.000484

AC XY:

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.0000963

Gnomad4 AMR

AF:

0.00183

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000647

Gnomad4 OTH

AF:

0.000948

Bravo

AF:

0.000593

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000582

AC:

ExAC

AF:

0.000502

AC:

EpiCase

AF:

0.000600

EpiControl

AF:

0.000533

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3Benign:1Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Surfactant metabolism dysfunction, pulmonary, 4

Uncertain:2Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 17, 2022	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 64 of the CSF2RA protein (p.Asp64Gly). This variant is present in population databases (no rsID available, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with CSF2RA-related conditions. ClinVar contains an entry for this variant (Variation ID: 573103). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CSF2RA protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Uncertain significance and reported on 12-04-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 07, 2021	- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

CSF2RA NM_001161531.1 exon 4 p.Asp64Gly (c.191A>G): This variant has not been reported in the literature but is present in 0.06% (79/126408) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/X-1404785-A-G). This variant is present in ClinVar (Variation ID:575469). Evolutionary conservation for this variant is limited or unavailable; computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

CSF2RA-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 15, 2024

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

-0.43

BayesDel_noAF

Benign

-0.43

CADD

Benign

4.6

DANN

Benign

0.45

DEOGEN2

Benign

0.17

T;.;T;T;T;.;T;.;.;.

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.67

.;T;.;T;T;T;T;T;T;T

M_CAP

Benign

0.010

MetaRNN

Benign

0.010

T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.26

MutationAssessor

Benign

0.55

N;N;N;.;N;N;.;N;N;N

MutationTaster

Benign

1.0

N;N;N;N;N;N;N;N;N;N

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.1

N;N;N;N;N;N;.;N;N;N

REVEL

Benign

0.14

Sift

Benign

0.59

T;T;T;T;T;T;.;T;T;T

Sift4G

Benign

0.22

T;D;T;T;T;T;T;T;T;T

Polyphen

0.29

B;.;B;.;B;P;.;P;B;P

Vest4

0.20

MVP

0.78

MPC

0.21

ClinPred

0.032

GERP RS

0.58

Varity_R

0.17

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over