ENST00000381500.6:c.974G>A

Variant names:

• chrX-1305473-G-A
• rs56960778
• ENST00000381500.6:c.974G>A
• CSF2RA p.Arg325His

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000381500.6(CSF2RA):​c.974G>A​(p.Arg325His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000804 in 1,613,898 control chromosomes in the GnomAD database, including 5 homozygotes. There are 626 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. R325S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0042 (2 hom., 306 hem., cov: 32)
  • Exomes 𝑓: 0.00045 (3 hom. 320 hem.)
• Consequence: CSF2RA ENST00000381500.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.45
• 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: Labcorp Genetics (formerly Invitae), ClinGen
• 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=0.004050523).
• BP6: Variant X-1305473-G-A is Benign according to our data. Variant chrX-1305473-G-A is described in ClinVar as Benign. ClinVar VariationId is 537346.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 = 0.00416 (633/152232) while in subpopulation AFR AF = 0.0147 (612/41534). AF 95% confidence interval is 0.0138. There are 2 homozygotes in GnomAd4. There are 306 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000381500.6. 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.1071G>A	p.Pro357Pro	synonymous	Exon 12 of 13	NP_758448.1	P15509-1
	CSF2RA	NM_001379167.1		c.974G>A	p.Arg325His	missense	Exon 12 of 13	NP_001366096.1	P15509-3
	CSF2RA	NM_001379168.1		c.974G>A	p.Arg325His	missense	Exon 10 of 11	NP_001366097.1	P15509-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSF2RA	ENST00000381500.6	TSL:1	c.974G>A	p.Arg325His	missense	Exon 9 of 10	ENSP00000370911.1	P15509-3
	CSF2RA	ENST00000355805.7	TSL:1	c.674G>A	p.Arg225His	missense	Exon 8 of 9	ENSP00000348058.2	P15509-6
	CSF2RA	ENST00000381529.9	TSL:1 MANE Select	c.1071G>A	p.Pro357Pro	synonymous	Exon 12 of 13	ENSP00000370940.3	P15509-1

Frequencies

GnomAD3 genomes AF: 0.00415 AC: 631 AN: 152114 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000918

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: 0.0000441

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00107 AC: 270 AN: 251168 AF XY: 0.000781

Gnomad AFR exome AF: 0.0146

Gnomad AMR exome AF: 0.000809

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000454 AC: 664 AN: 1461666 Hom.: 3 Cov.: 32 AF XY: 0.000440 AC XY: 320 AN XY: 727142

African (AFR) AF: 0.0169 AC: 567 AN: 33472

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

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86250

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

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5762

European-Non Finnish (NFE) AF: 0.0000144 AC: 16 AN: 1111838

Other (OTH) AF: 0.000662 AC: 40 AN: 60378

GnomAD4 genome AF: 0.00416 AC: 633 AN: 152232 Hom.: 2 Cov.: 32 AF XY: 0.00411 AC XY: 306 AN XY: 74428

African (AFR) AF: 0.0147 AC: 612 AN: 41534

American (AMR) AF: 0.000916 AC: 14 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68024

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Bravo AF: 0.00474

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	0.18
DANN	Benign	0.35
FATHMM_MKL	Benign	0.0011	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-0.29	T
PhyloP100		-2.4
PROVEAN	Benign	0.12	N
REVEL	Benign	0.088
Sift	Benign	0.16	T
Sift4G	Benign	0.25	T

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: rs56960778;

hg19: chrX-1424366;

COSMIC: COSV62626457;

COSMIC: COSV62626457;