NM_172245.4:c.425C>T

Variant names:

• chrX-1288840-C-T
• rs151058706
• NM_172245.4:c.425C>T

Variant summary

Our verdict is Benign. The variant received -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. 12/18 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. 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:6
• Conservation: PhyloP100: -0.225
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• surfactant metabolism dysfunction, pulmonary, 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• hereditary pulmonary alveolar proteinosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 40 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_172245.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSF2RA	NM_172245.4	MANE Select	c.425C>T	p.Pro142Leu	missense	Exon 6 of 13	NP_758448.1	P15509-1
	CSF2RA	NM_001161530.2		c.425C>T	p.Pro142Leu	missense	Exon 6 of 14	NP_001155002.1	P15509-7
	CSF2RA	NM_001379153.1		c.425C>T	p.Pro142Leu	missense	Exon 5 of 13	NP_001366082.1	P15509-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSF2RA	ENST00000381529.9	TSL:1 MANE Select	c.425C>T	p.Pro142Leu	missense	Exon 6 of 13	ENSP00000370940.3	P15509-1
	CSF2RA	ENST00000381509.8	TSL:1	c.425C>T	p.Pro142Leu	missense	Exon 6 of 13	ENSP00000370920.3	P15509-2
	CSF2RA	ENST00000381524.8	TSL:1	c.425C>T	p.Pro142Leu	missense	Exon 6 of 13	ENSP00000370935.3	P15509-1

Frequencies

GnomAD3 genomes AF: 0.0125 AC: 1904 AN: 152124 Hom.: 40 Cov.: 32

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

GnomAD2 exomes AF: 0.00336 AC: 843 AN: 251094 AF XY: 0.00231

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 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

African (AFR) AF: 0.0492 AC: 1645 AN: 33468

American (AMR) AF: 0.00253 AC: 113 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86250

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5762

European-Non Finnish (NFE) AF: 0.0000800 AC: 89 AN: 1111830

Other (OTH) AF: 0.00283 AC: 171 AN: 60378

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

African (AFR) AF: 0.0437 AC: 1813 AN: 41526

American (AMR) AF: 0.00452 AC: 69 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68032

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	2	Surfactant metabolism dysfunction, pulmonary, 4 (2)

Computational scores

Source: dbNSFP v4.9

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
FATHMM_MKL	Benign	0.0015	N
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	1.6	L
PhyloP100		-0.23
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-4.3	D
REVEL	Benign	0.11
Sift	Benign	0.096	T
Sift4G	Benign	0.15	T
Polyphen		0.55	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

Other links and lift over

dbSNP: rs151058706; hg19: chrX-1407733; COSMIC: COSV62626839; COSMIC: COSV62626839;