rs150743648

Variant names:

• chrX-1285892-A-G
• rs150743648
• NM_172245.4:c.191A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_172245.4(CSF2RA):​c.191A>G​(p.Asp64Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000501 in 1,613,860 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 384 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00056 (0 hom., 36 hem., cov: 31)
  • Exomes 𝑓: 0.00049 (0 hom. 348 hem.)
• Consequence: CSF2RA NM_172245.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3 B:1 O:1
• Conservation: PhyloP100: 0.0610
• 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010257632).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000559 (85/152192) while in subpopulation AMR AF = 0.00183 (28/15262). AF 95% confidence interval is 0.0013. There are 0 homozygotes in GnomAd4. There are 36 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Hemizygotes in GnomAd4 at 36 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.191A>G	p.Asp64Gly	missense	Exon 4 of 13	NP_758448.1	P15509-1
	CSF2RA	NM_001161530.2		c.191A>G	p.Asp64Gly	missense	Exon 4 of 14	NP_001155002.1	P15509-7
	CSF2RA	NM_001379153.1		c.191A>G	p.Asp64Gly	missense	Exon 3 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.191A>G	p.Asp64Gly	missense	Exon 4 of 13	ENSP00000370940.3	P15509-1
	CSF2RA	ENST00000381509.8	TSL:1	c.191A>G	p.Asp64Gly	missense	Exon 4 of 13	ENSP00000370920.3	P15509-2
	CSF2RA	ENST00000381524.8	TSL:1	c.191A>G	p.Asp64Gly	missense	Exon 4 of 13	ENSP00000370935.3	P15509-1

Frequencies

GnomAD3 genomes AF: 0.000559 AC: 85 AN: 152074 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00184

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.000545 AC: 137 AN: 251176 AF XY: 0.000560

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00173

Gnomad ASJ exome AF: 0.000595

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000555

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000495 AC: 723 AN: 1461668 Hom.: 0 Cov.: 40 AF XY: 0.000479 AC XY: 348 AN XY: 727142

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00154 AC: 69 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.000421 AC: 11 AN: 26132

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

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86248

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

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5762

European-Non Finnish (NFE) AF: 0.000559 AC: 621 AN: 1111840

Other (OTH) AF: 0.000282 AC: 17 AN: 60378

GnomAD4 genome AF: 0.000559 AC: 85 AN: 152192 Hom.: 0 Cov.: 31 AF XY: 0.000484 AC XY: 36 AN XY: 74424

African (AFR) AF: 0.0000963 AC: 4 AN: 41532

American (AMR) AF: 0.00183 AC: 28 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

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: 0.000647 AC: 44 AN: 68004

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Bravo AF: 0.000593

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.000502 AC: 61

EpiCase AF: 0.000600

EpiControl AF: 0.000533

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Surfactant metabolism dysfunction, pulmonary, 4 (3)
-	-	1	CSF2RA-related disorder (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	4.6
DANN	Benign	0.45
DEOGEN2	Benign	0.17	T
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.010	T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.061
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.14
Sift	Benign	0.59	T
Sift4G	Benign	0.22	T
Polyphen		0.29	B
Vest4		0.20
MVP		0.78
MPC		0.21
ClinPred		0.032	T
GERP RS		0.58
Varity_R		0.17
Mutation Taster		=85/15	polymorphism

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: rs150743648; hg19: chrX-1404785;