ENST00000355432.8:c.1073G>A

Variant names:

• chrX-1309528-G-A
• rs28722602
• ENST00000355432.8:c.1073G>A
• CSF2RA p.Arg358Gln

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000355432.8(CSF2RA):​c.1073G>A​(p.Arg358Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0121 in 1,613,780 control chromosomes in the GnomAD database, including 195 homozygotes. There are 10,195 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R358L) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0091 (9 hom., 703 hem., cov: 33)
  • Exomes 𝑓: 0.012 (186 hom. 9492 hem.)
• Consequence: CSF2RA ENST00000355432.8 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.816
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028986335).
• BP6: Variant X-1309528-G-A is Benign according to our data. Variant chrX-1309528-G-A is described in ClinVar as Benign. ClinVar VariationId is 3036043.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00915 (1392/152192) while in subpopulation SAS AF = 0.0324 (156/4822). AF 95% confidence interval is 0.0282. There are 9 homozygotes in GnomAd4. There are 703 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000355432.8. 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.*49G>A		3_prime_UTR	Exon 13 of 13	NP_758448.1	P15509-1
	CSF2RA	NM_172246.4		c.1073G>A	p.Arg358Gln	missense	Exon 11 of 11	NP_758449.1	P15509-5
	CSF2RA	NM_001161530.2		c.*49G>A		3_prime_UTR	Exon 14 of 14	NP_001155002.1	P15509-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSF2RA	ENST00000355432.8	TSL:1	c.1073G>A	p.Arg358Gln	missense	Exon 11 of 11	ENSP00000347606.3	P15509-5
	CSF2RA	ENST00000381529.9	TSL:1 MANE Select	c.*49G>A		3_prime_UTR	Exon 13 of 13	ENSP00000370940.3	P15509-1
	CSF2RA	ENST00000381524.8	TSL:1	c.*49G>A		3_prime_UTR	Exon 13 of 13	ENSP00000370935.3	P15509-1

Frequencies

GnomAD3 genomes AF: 0.00916 AC: 1393 AN: 152074 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.00242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00936

Gnomad ASJ AF: 0.0135

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0325

Gnomad FIN AF: 0.0104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0120

Gnomad OTH AF: 0.00957

GnomAD2 exomes AF: 0.0116 AC: 2901 AN: 251160 AF XY: 0.0131

Gnomad AFR exome AF: 0.00197

Gnomad AMR exome AF: 0.00581

Gnomad ASJ exome AF: 0.0137

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00924

Gnomad NFE exome AF: 0.0117

Gnomad OTH exome AF: 0.0114

GnomAD4 exome AF: 0.0124 AC: 18193 AN: 1461588 Hom.: 186 Cov.: 33 AF XY: 0.0131 AC XY: 9492 AN XY: 727078

African (AFR) AF: 0.00179 AC: 60 AN: 33472

American (AMR) AF: 0.00749 AC: 335 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0135 AC: 353 AN: 26132

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39698

South Asian (SAS) AF: 0.0302 AC: 2604 AN: 86246

European-Finnish (FIN) AF: 0.0105 AC: 562 AN: 53420

Middle Eastern (MID) AF: 0.00503 AC: 29 AN: 5762

European-Non Finnish (NFE) AF: 0.0122 AC: 13562 AN: 1111768

Other (OTH) AF: 0.0113 AC: 683 AN: 60374

GnomAD4 genome AF: 0.00915 AC: 1392 AN: 152192 Hom.: 9 Cov.: 33 AF XY: 0.00945 AC XY: 703 AN XY: 74420

African (AFR) AF: 0.00241 AC: 100 AN: 41508

American (AMR) AF: 0.00935 AC: 143 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0135 AC: 47 AN: 3470

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5174

South Asian (SAS) AF: 0.0324 AC: 156 AN: 4822

European-Finnish (FIN) AF: 0.0104 AC: 110 AN: 10604

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

European-Non Finnish (NFE) AF: 0.0120 AC: 814 AN: 68002

Other (OTH) AF: 0.00947 AC: 20 AN: 2112

EpiCase AF: 0.00987

EpiControl AF: 0.0113

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	CSF2RA-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.90	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.71
DANN	Benign	0.69
FATHMM_MKL	Benign	0.0017	N
LIST_S2	Benign	0.30	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.82
PROVEAN	Benign	0.21	N
REVEL	Benign	0.019
Sift	Pathogenic	0.0	D

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs28722602;

hg19: chrX-1428421;

COSMIC: COSV62624509;

COSMIC: COSV62624509;