NM_172245.4:c.999G>A

Variant names:

• chrX-1303975-G-A
• rs28460440
• NM_172245.4:c.999G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_172245.4(CSF2RA):​c.999G>A​(p.Val333Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.399 in 1,611,098 control chromosomes in the GnomAD database, including 130,600 homozygotes. There are 318,614 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (10490 hom., 26891 hem., cov: 28)
  • Exomes 𝑓: 0.40 (120110 hom. 291723 hem.)
• Consequence: CSF2RA NM_172245.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 0.337
• 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=-0.88).
• BP6: Variant X-1303975-G-A is Benign according to our data. Variant chrX-1303975-G-A is described in ClinVar as Benign. ClinVar VariationId is 178717.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.337 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.415 is higher than 0.05.

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.999G>A	p.Val333Val	synonymous	Exon 11 of 13	NP_758448.1
	CSF2RA	NM_001161530.2		c.1101G>A	p.Val367Val	synonymous	Exon 12 of 14	NP_001155002.1
	CSF2RA	NM_001379153.1		c.1101G>A	p.Val367Val	synonymous	Exon 11 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.999G>A	p.Val333Val	synonymous	Exon 11 of 13	ENSP00000370940.3
	CSF2RA	ENST00000381509.8	TSL:1	c.999G>A	p.Val333Val	synonymous	Exon 11 of 13	ENSP00000370920.3
	CSF2RA	ENST00000381524.8	TSL:1	c.999G>A	p.Val333Val	synonymous	Exon 11 of 13	ENSP00000370935.3

Frequencies

GnomAD3 genomes AF: 0.369 AC: 55455 AN: 150282 Hom.: 10486 Cov.: 28

Gnomad AFR AF: 0.288

Gnomad AMI AF: 0.449

Gnomad AMR AF: 0.333

Gnomad ASJ AF: 0.381

Gnomad EAS AF: 0.334

Gnomad SAS AF: 0.311

Gnomad FIN AF: 0.444

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.419

Gnomad OTH AF: 0.385

GnomAD2 exomes AF: 0.373 AC: 93680 AN: 251110 AF XY: 0.376

Gnomad AFR exome AF: 0.283

Gnomad AMR exome AF: 0.296

Gnomad ASJ exome AF: 0.367

Gnomad EAS exome AF: 0.355

Gnomad FIN exome AF: 0.449

Gnomad NFE exome AF: 0.412

Gnomad OTH exome AF: 0.388

GnomAD4 exome AF: 0.403 AC: 588155 AN: 1460694 Hom.: 120110 Cov.: 48 AF XY: 0.402 AC XY: 291723 AN XY: 726492

African (AFR) AF: 0.285 AC: 9530 AN: 33446

American (AMR) AF: 0.303 AC: 13536 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.373 AC: 9734 AN: 26106

East Asian (EAS) AF: 0.295 AC: 11690 AN: 39692

South Asian (SAS) AF: 0.328 AC: 28264 AN: 86214

European-Finnish (FIN) AF: 0.438 AC: 23411 AN: 53406

Middle Eastern (MID) AF: 0.390 AC: 2243 AN: 5758

European-Non Finnish (NFE) AF: 0.419 AC: 466032 AN: 1111022

Other (OTH) AF: 0.393 AC: 23715 AN: 60338

GnomAD4 genome AF: 0.369 AC: 55464 AN: 150404 Hom.: 10490 Cov.: 28 AF XY: 0.367 AC XY: 26891 AN XY: 73284

African (AFR) AF: 0.287 AC: 11762 AN: 40946

American (AMR) AF: 0.333 AC: 5005 AN: 15034

Ashkenazi Jewish (ASJ) AF: 0.381 AC: 1315 AN: 3452

East Asian (EAS) AF: 0.334 AC: 1678 AN: 5028

South Asian (SAS) AF: 0.312 AC: 1479 AN: 4746

European-Finnish (FIN) AF: 0.444 AC: 4593 AN: 10344

Middle Eastern (MID) AF: 0.398 AC: 117 AN: 294

European-Non Finnish (NFE) AF: 0.419 AC: 28321 AN: 67590

Other (OTH) AF: 0.382 AC: 789 AN: 2068

Bravo AF: 0.362

EpiCase AF: 0.425

EpiControl AF: 0.426

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (3)
-	-	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	-0.88
CADD	Benign	0.64
DANN	Benign	0.74
PhyloP100		0.34

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: rs28460440; hg19: chrX-1422868; COSMIC: COSV62625891; COSMIC: COSV62625891;