X-1288840-C-T

Variant summary

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

The NM_172245.4(CSF2RA):c.425C>T(p.Pro142Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00245 in 1,613,894 control chromosomes in the GnomAD database, including 87 homozygotes. There are 1,737 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P142Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.013 (40 hom., 889 hem., cov: 32)
  • Exomes 𝑓: 0.0014 (47 hom. 848 hem.)
• Consequence: CSF2RA NM_172245.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.225

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=0.0035214424).
• BP6: Variant X-1288840-C-T is Benign according to our data. Variant chrX-1288840-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 178715.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 = 0.0125 (1907/152242) while in subpopulation AFR AF= 0.0437 (1813/41526). AF 95% confidence interval is 0.042. There are 40 homozygotes in gnomad4. There are 889 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 40 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CSF2RA	NM_172245.4	c.425C>T	p.Pro142Leu	missense_variant	6/13	ENST00000381529.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CSF2RA	ENST00000381529.9	c.425C>T	p.Pro142Leu	missense_variant	6/13	1	NM_172245.4	A2

Frequencies

GnomAD3 genomes AF: 0.0125 AC: 1904 AN: 152124 Hom.: 40 Cov.: 32 AF XY: 0.0119 AC XY: 885 AN XY: 74312

Gnomad AFR AF: 0.0437

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00452

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00336 AC: 843 AN: 251094 Hom.: 19 AF XY: 0.00231 AC XY: 313 AN XY: 135734

Gnomad AFR exome AF: 0.0463

Gnomad AMR exome AF: 0.00205

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000794

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00140 AC: 2040 AN: 1461652 Hom.: 47 Cov.: 34 AF XY: 0.00117 AC XY: 848 AN XY: 727138

Gnomad4 AFR exome AF: 0.0492

Gnomad4 AMR exome AF: 0.00253

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000800

Gnomad4 OTH exome AF: 0.00283

GnomAD4 genome AF: 0.0125 AC: 1907 AN: 152242 Hom.: 40 Cov.: 32 AF XY: 0.0119 AC XY: 889 AN XY: 74440

Gnomad4 AFR AF: 0.0437

Gnomad4 AMR AF: 0.00452

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00662

Bravo AF: 0.0143

ESP6500AA AF: 0.0477 AC: 210

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00405 AC: 492

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Surfactant metabolism dysfunction, pulmonary, 4 Benign:2

Benign, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Mar 05, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 21, 2013

Pro142Leu in exon 7 of CSF2RA: This variant is not expected to have clinical sig nificance because it has been identified in 4.8% (210/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs151058706). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	1.9
Dann	Benign	0.97
DEOGEN2	Uncertain	0.52	D;.;.;D;D;D;.;.;.;.
FATHMM_MKL	Benign	0.0015	N
MetaRNN	Benign	0.0035	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	1.6	L;.;L;L;.;L;L;L;L;L
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-4.3	D;D;D;D;D;D;D;D;D;D
REVEL	Benign	0.11
Sift	Benign	0.096	T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.15	T;T;T;T;T;T;T;T;T;T
Polyphen		0.55	P;.;.;P;.;P;P;P;P;P
Vest4		0.21
MVP		0.72
MPC		0.45
ClinPred		0.026	T
GERP RS		-3.6
Varity_R		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs151058706; hg19: chrX-1407733; COSMIC: COSV62626839; COSMIC: COSV62626839;