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rs149974131

chrX-1294373-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2

The NM_172245.4(CSF2RA):c.692C>T(p.Thr231Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000519 in 1,613,734 control chromosomes in the GnomAD database, including 1 homozygotes. There are 412 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T231T) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00025 ( 0 hom., 22 hem., cov: 32)
Exomes 𝑓: 0.00055 ( 1 hom. 390 hem. )

Consequence

CSF2RA
NM_172245.4 missense

Scores

5
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.47
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (MetaRNN=0.15778312).
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00025 (38/152182) while in subpopulation NFE AF= 0.000426 (29/68036). AF 95% confidence interval is 0.000304. There are 0 homozygotes in gnomad4. There are 22 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High Hemizygotes in GnomAd at 22 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CSF2RANM_172245.4 linkuse as main transcriptc.692C>T p.Thr231Met missense_variant 8/13 ENST00000381529.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CSF2RAENST00000381529.9 linkuse as main transcriptc.692C>T p.Thr231Met missense_variant 8/131 NM_172245.4 A2P15509-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000250
AC:
38
AN:
152182
Hom.:
0
Cov.:
32
AF XY:
0.000296
AC XY:
22
AN XY:
74350
show subpopulations
Gnomad AFR
AF:
0.000169
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000941
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000426
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000259
AC:
65
AN:
251176
Hom.:
0
AF XY:
0.000295
AC XY:
40
AN XY:
135744
show subpopulations
Gnomad AFR exome
AF:
0.000308
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000217
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000924
Gnomad NFE exome
AF:
0.000449
Gnomad OTH exome
AF:
0.000489
GnomAD4 exome
AF:
0.000547
AC:
800
AN:
1461552
Hom.:
1
Cov.:
32
AF XY:
0.000536
AC XY:
390
AN XY:
727090
show subpopulations
Gnomad4 AFR exome
AF:
0.0000896
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000227
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.000150
Gnomad4 NFE exome
AF:
0.000670
Gnomad4 OTH exome
AF:
0.000580
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000250
AC:
38
AN:
152182
Hom.:
0
Cov.:
32
AF XY:
0.000296
AC XY:
22
AN XY:
74350
show subpopulations
Gnomad4 AFR
AF:
0.000169
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000941
Gnomad4 NFE
AF:
0.000426
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.000329
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.000582
AC:
5
ExAC
?
    Exome Aggregation Consortium database
AF:
0.000231
AC:
28
EpiCase
AF:
0.000327
EpiControl
AF:
0.000356

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Surfactant metabolism dysfunction, pulmonary, 4 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeAug 23, 2022This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 231 of the CSF2RA protein (p.Thr231Met). This variant is present in population databases (no rsID available, gnomAD 0.05%). 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: 578948). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.20
T
BayesDel_noAF
Benign
-0.19
Cadd
Benign
17
Dann
Benign
0.91
DEOGEN2
Benign
0.30
T;.;.;T;T;T;.;.;.
FATHMM_MKL
Benign
0.043
N
M_CAP
Benign
0.056
D
MetaRNN
Benign
0.16
T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
0.070
D
MutationAssessor
Benign
1.1
L;.;L;L;.;L;L;L;L
MutationTaster
Benign
1.0
N;N;N;N;N;N;N;N;N;N
PrimateAI
Uncertain
0.54
T
PROVEAN
Uncertain
-3.0
D;D;D;D;D;D;D;D;D
REVEL
Benign
0.14
Sift
Uncertain
0.027
D;D;D;D;D;D;D;D;D
Sift4G
Uncertain
0.044
D;T;D;D;D;D;D;D;D
Polyphen
0.38
B;.;.;B;.;B;B;P;B
Vest4
0.33
MVP
0.64
MPC
0.17
ClinPred
0.034
T
GERP RS
1.5
Varity_R
0.076

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.

Other links and lift over

dbSNP: rs149974131; hg19: chrX-1413266; COSMIC: COSV62623706; COSMIC: COSV62623706; API