X-1294349-A-T

Variant names:

• chrX-1294349-A-T
• rs768648388
• NM_172245.4:c.668A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_172245.4(CSF2RA):​c.668A>T​(p.Asn223Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,470 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N223S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom. 0 hem.)
• Consequence: CSF2RA NM_172245.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.13
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.668A>T	p.Asn223Ile	missense	Exon 8 of 13	NP_758448.1
	CSF2RA	NM_001161530.2		c.668A>T	p.Asn223Ile	missense	Exon 8 of 14	NP_001155002.1
	CSF2RA	NM_001379153.1		c.668A>T	p.Asn223Ile	missense	Exon 7 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.668A>T	p.Asn223Ile	missense	Exon 8 of 13	ENSP00000370940.3
	CSF2RA	ENST00000381509.8	TSL:1	c.668A>T	p.Asn223Ile	missense	Exon 8 of 13	ENSP00000370920.3
	CSF2RA	ENST00000381524.8	TSL:1	c.668A>T	p.Asn223Ile	missense	Exon 8 of 13	ENSP00000370935.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251178 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461470 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727056

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44716

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

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5604

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111838

Other (OTH) AF: 0.00 AC: 0 AN: 60362

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.42	T
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.025	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		2.1
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Benign	0.28
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.59
MutPred		0.68		Gain of catalytic residue at V224 (P = 0.0539)
MVP		0.71
MPC		0.63
ClinPred		0.95	D
GERP RS		1.5
Varity_R		0.58
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs768648388; hg19: chrX-1413242;