rs149059494

Variant names:

• chrX-1288522-A-G
• rs149059494
• NM_172245.4:c.223A>G

Your query was ambiguous. Multiple possible variants found:

• chrX-1288522-A-G
• chrX-1288522-A-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.223A>G​(p.Ser75Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.002 in 1,613,948 control chromosomes in the GnomAD database, including 67 homozygotes. There are 1,439 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S75R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.010 (33 hom., 740 hem., cov: 32)
  • Exomes 𝑓: 0.0011 (34 hom. 699 hem.)
• Consequence: CSF2RA NM_172245.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.106
• 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=0.003208667).
• BP6: Variant X-1288522-A-G is Benign according to our data. Variant chrX-1288522-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 469625.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 = 0.0104 (1587/152282) while in subpopulation AFR AF = 0.0359 (1491/41554). AF 95% confidence interval is 0.0344. There are 33 homozygotes in GnomAd4. There are 740 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 33 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.223A>G	p.Ser75Gly	missense	Exon 5 of 13	NP_758448.1	P15509-1
	CSF2RA	NM_001161530.2		c.223A>G	p.Ser75Gly	missense	Exon 5 of 14	NP_001155002.1	P15509-7
	CSF2RA	NM_001379153.1		c.223A>G	p.Ser75Gly	missense	Exon 4 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.223A>G	p.Ser75Gly	missense	Exon 5 of 13	ENSP00000370940.3	P15509-1
	CSF2RA	ENST00000381509.8	TSL:1	c.223A>G	p.Ser75Gly	missense	Exon 5 of 13	ENSP00000370920.3	P15509-2
	CSF2RA	ENST00000381524.8	TSL:1	c.223A>G	p.Ser75Gly	missense	Exon 5 of 13	ENSP00000370935.3	P15509-1

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1569 AN: 152164 Hom.: 30 Cov.: 32

Gnomad AFR AF: 0.0355

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00472

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00908

GnomAD2 exomes AF: 0.00296 AC: 743 AN: 251178 AF XY: 0.00211

Gnomad AFR exome AF: 0.0400

Gnomad AMR exome AF: 0.00197

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.00112 AC: 1637 AN: 1461666 Hom.: 34 Cov.: 33 AF XY: 0.000961 AC XY: 699 AN XY: 727146

African (AFR) AF: 0.0389 AC: 1301 AN: 33468

American (AMR) AF: 0.00219 AC: 98 AN: 44716

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

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86250

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

Middle Eastern (MID) AF: 0.00278 AC: 16 AN: 5762

European-Non Finnish (NFE) AF: 0.0000522 AC: 58 AN: 1111842

Other (OTH) AF: 0.00257 AC: 155 AN: 60378

GnomAD4 genome AF: 0.0104 AC: 1587 AN: 152282 Hom.: 33 Cov.: 32 AF XY: 0.00994 AC XY: 740 AN XY: 74460

African (AFR) AF: 0.0359 AC: 1491 AN: 41554

American (AMR) AF: 0.00471 AC: 72 AN: 15286

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68020

Other (OTH) AF: 0.00899 AC: 19 AN: 2114

Bravo AF: 0.0119

ESP6500AA AF: 0.0334 AC: 147

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00356 AC: 432

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	Surfactant metabolism dysfunction, pulmonary, 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	0.19
DANN	Benign	0.45
DEOGEN2	Benign	0.21	T
FATHMM_MKL	Benign	0.0071	N
LIST_S2	Benign	0.41	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.11
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.17
Sift	Benign	0.19	T
Sift4G	Uncertain	0.058	T
Polyphen		0.48	P
Vest4		0.14
MVP		0.67
MPC		0.12
ClinPred		0.013	T
GERP RS		-1.2
Varity_R		0.12

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: rs149059494; hg19: chrX-1407415;