rs139093878

Variant names:

• chrX-1290412-G-C
• rs139093878
• NM_172245.4:c.549G>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_172245.4(CSF2RA):​c.549G>C​(p.Leu183Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00048 in 1,613,696 control chromosomes in the GnomAD database, including 1 homozygotes. There are 322 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., 176 hem., cov: 32)
  • Exomes 𝑓: 0.00025 (0 hom. 146 hem.)
• Consequence: CSF2RA NM_172245.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.887
• 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: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• hereditary pulmonary alveolar proteinosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant X-1290412-G-C is Benign according to our data. Variant chrX-1290412-G-C is described in ClinVar as Benign. ClinVar VariationId is 226542.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.887 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00267 (407/152216) while in subpopulation AFR AF = 0.00929 (386/41538). AF 95% confidence interval is 0.00853. There are 1 homozygotes in GnomAd4. There are 176 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 176 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSF2RA	NM_172245.4	MANE Select	c.549G>C	p.Leu183Leu	synonymous	Exon 7 of 13	NP_758448.1
	CSF2RA	NM_001161530.2		c.549G>C	p.Leu183Leu	synonymous	Exon 7 of 14	NP_001155002.1
	CSF2RA	NM_001379153.1		c.549G>C	p.Leu183Leu	synonymous	Exon 6 of 13	NP_001366082.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSF2RA	ENST00000381529.9	TSL:1 MANE Select	c.549G>C	p.Leu183Leu	synonymous	Exon 7 of 13	ENSP00000370940.3
	CSF2RA	ENST00000381509.8	TSL:1	c.549G>C	p.Leu183Leu	synonymous	Exon 7 of 13	ENSP00000370920.3
	CSF2RA	ENST00000381524.8	TSL:1	c.549G>C	p.Leu183Leu	synonymous	Exon 7 of 13	ENSP00000370935.3

Frequencies

GnomAD3 genomes AF: 0.00266 AC: 405 AN: 152098 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00927

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000985

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: 0.0000588

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000721 AC: 181 AN: 251178 AF XY: 0.000597

Gnomad AFR exome AF: 0.00960

Gnomad AMR exome AF: 0.000636

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000252 AC: 368 AN: 1461480 Hom.: 0 Cov.: 32 AF XY: 0.000201 AC XY: 146 AN XY: 727046

African (AFR) AF: 0.00872 AC: 292 AN: 33468

American (AMR) AF: 0.000783 AC: 35 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111672

Other (OTH) AF: 0.000613 AC: 37 AN: 60368

GnomAD4 genome AF: 0.00267 AC: 407 AN: 152216 Hom.: 1 Cov.: 32 AF XY: 0.00236 AC XY: 176 AN XY: 74420

African (AFR) AF: 0.00929 AC: 386 AN: 41538

American (AMR) AF: 0.000984 AC: 15 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68018

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Bravo AF: 0.00296

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Surfactant metabolism dysfunction, pulmonary, 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.087
DANN	Benign	0.51
PhyloP100		-0.89

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

Other links and lift over

dbSNP: rs139093878; hg19: chrX-1409305;